Failing kidneys: renal replacement therapies in the ICU

Introduction

Acute kidney injury (AKI) impacts between a third and a half of all intensive care unit (ICU) patients with approximately 20% of patients requiring renal replacement therapy (RRT).1 It is one of the most common organ dysfunctions experienced by critically ill or injured surgical patients. Within the trauma population, incidence is greatly impacted by the type of injury with AKI occurring in up to 25% of ICU patients after blunt trauma and 40% of burn patients.2 A recent cohort study of patients presenting to a level 1 trauma center demonstrated an AKI incidence of 45%. 69% of the AKI group (31% of all patients) had signs of renal dysfunction at admission, but the majority experienced renal recovery within 2 days.3 The incidence of AKI after surgery ranges from 5% after major abdominal surgeries to nearly 50% after orthotopic liver transplantation.2 Common causes of AKI in the post-trauma and postsurgical groups include acute tubular necrosis resulting from renal ischemia secondary to hypovolemia, hemorrhage, or shock state, systemic inflammatory response, and nephrotoxic agents including many medications especially antibiotics and non-steroidal anti-inflammatory drugs and myoglobin from rhabdomyolysis.2 The presence of AKI increases overall hospital mortality. A recent Trauma Quality Improvement Process (TQIP) analysis of patients with severe AKI demonstrated a mortality rate of 28%.4 The risk of death increases to 50% among all ICU patients with AKI requiring RRT within the first week of ICU admission.1

Diagnosis and classification of AKI

There have been varying definitions to diagnosis and classify AKI. Three of the most used systems include Risk, Injury, Failure, Loss of Kidney Function, and End-stage Kidney Disease (RIFLE), Acute Kidney Injury Network (AKIN), and Kidney Disease: Improving Global Outcomes (KDIGO). They all incorporate some combination of timing of renal dysfunction onset, glomerular filtration rate (GFR), serum creatinine, and urine output (UOP) into their assessment strategy. The RIFLE classification system was first introduced in 2004 by the Acute Dialysis Quality Initiative group. This system defined AKI as a rise in serum creatinine by greater than 50% over 7 days and focused on levels of decreased GFR and UOP along with rising creatinine to define the stages of AKI—Risk, Injury and Failure. The AKIN modified RIFLE in 2007. Key elements included shortening the initial time of symptoms to 48 hours, decreasing the initial rise in serum creatinine to 0.3, and excluding GFR. More recently, there has been a push towards adoption of the KDIGO Acute Kidney Injury Group classification system, which aims to blend the RIFLE and AKIN criteria into a single unified definition of AKI. Table 1 highlights the commonalities and differences between these systems. Comparison studies in critically ill patients have noted that application of KDIGO leads to an increased diagnosis of AKI and is more predictive of in-hospital mortality.5

Recently, biomarkers are being incorporated along with the functional metrics of UOP and serum creatinine to identify patients at high risk for AKI. An elevated urinary [TIMP2]∙[IGFBP7]—a marker for cell-cycle arrest, predicts AKI after cardiac surgery and non-cardiac surgery.6 Specific biomarkers for kidney tubular injury—neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule 1 (KIM-1), and α-glutathione s-transferase (GST) and π-GST—can be detected prior to changes in serum creatinine and can predict AKI progression and severity.6 NGAL is available as a point of care test allowing for rapid identification of AKI. This early detection can allow for prompt interventions to treat the AKI and allow for measures to prevent additional injury. A cohort study including 294 patients after major study demonstrated significantly increased early recovery of AKI and reduction in ICU length of stay using a tiered renal protection strategy guided by levels of urinary [TIMP2]∙[IGFBP7].7 Additional ongoing trials are looking at how specific biomarkers can identify AKI cause, guide targeted therapies, and provide prognostication information regarding renal recovery resulting in personalized treatment for AKI.8

When to initiate RRT

There are several commonly accepted triggers to initiate RRT. These include severe acidosis defined by a pH<7.2 or serum bicarbonate <12 mmol/L, serum potassium >6.0 mmol/L, severe azotemia with complications including encephalopathy or pericarditis, and fluid overload state marked by respiratory dysfunction with a PaO₂/FiO₂<200.

The question arises when to initiate RRT in critically ill patients with AKI without these severe complications. The hypothesized advantage to early RRT prior to major complications is to restore a balanced physiologic state, avoid exposure to metabolic toxicities, and mitigate the negative consequences of positive fluid balance. The major point advocating for delayed RRT is that many patients may recover renal function if given an appropriate period of supportive care, thus completely avoiding RRT and its accompanying risks. Several randomized controlled trials—ELAIN,9 AKIKI,10 IDEAL-ICU,11 STARRT-AKI,12 AKIKI 213—have been completed during the past 10 years to examine what other factors should direct the ideal timing of RRT initiation in this group. Table 2 summarizes key aspects and findings of each study.

The most recent studies are STARRT-AKI and AKIKI 2. STARRT-AKI included 3019 patients across 168 hospitals in 15 countries that were randomized to early versus late RRT initiation.12 Patients qualified for RRT if meeting KDIGO stage 2 or 3 AKI criteria. The early group received therapy at a median of 6.1 hours versus the delayed group at a median of 31.1 hours. Key findings in this study include no advantage to early initiation of RRT. There was no decrease in 90-day mortality and no difference in ventilator-free days, vasoactive-free days, or ICU-free days at 28 days. Also notable, there were less adverse events in the delayed group and over 35% of patients in the delayed group never received RRT due to renal recovery or death.

Noting that the longer RRT was delayed resulted in more patients avoiding therapy, AKIKI 2 pushed the delay to RRT initiation even further. This study included 278 patients across 39 ICUs in France.13 Patients with KDIGO stage 3 AKI were eligible and randomized to delayed versus more delayed RRT once they met one of the following criteria: oliguria or anuria for more than 72 hours or Blood Urea Nitrogen (BUN) between 112 and 140. These were the same criteria for RRT initiation in the delayed group of the initial AKIKI trial. The delayed group received RRT at a median time of 44 hours from meeting KDIGO stage 3 AKI criteria and 3 hours from randomization. The more delayed group triggers for RRT were the standard criteria including severe acidosis, electrolyte disorders, pulmonary dysfunction due to edema, or BUN>140. This group received RRT at a median of 94 hours from meeting KDIGO stage 3 AKI criteria and 33 hours from randomization. Key findings demonstrated an increase in adjusted 60-day mortality in the more delayed strategy group. These two studies demonstrated that while early RRT does not afford improved outcomes, a more delayed strategy may be associated with potential harm. KDIGO stage 3 AKI does not mandate immediate RRT; however, if no renal recovery is noted after 48–72 hours, initiation of RRT will likely benefit the patient.

What is the best access?

Once deciding a patient requires RRT, the next step is choosing the best access. The goal is to maximize blood flow rates and minimize complications such as infection and line thrombosis. The KDIGO guidelines recommend preferential placement in the right internal jugular vein, followed by either femoral vein, and lastly the left internal jugular vein.14 When placing a jugular catheter, the tip of the catheter should ideally be placed in the right atrium, while a femoral catheter should terminate in the inferior vena cava. Subclavian access is discouraged due to the risk of vein stenosis, potentially limiting long-term fistula options if needed. While femoral catheters have been associated with increased infection in the past, recent studies have shown similar rates of catheter infection regardless of site, except in morbidly obese patients. It is critical to use sterile techniques and maximal protective barriers when placing these catheters.

Two major types of catheters are available for RRTs distinguished by the presence of a cuff, if they require tunneling during placement, and optimal duration of use. Most commonly used for RRT initiation is a non-tunneled, non-cuffed dialysis catheter. These are easily placed at the beside under ultrasound guidance by an intensivist. These are considered temporary and should be removed prior to hospital discharge. The alternative, tunneled, cuffed dialysis catheters are placed under fluoroscopic guidance usually by an interventional radiologist or surgeon. Tunneled, cuffed dialysis catheters are associated with decreased risk of infection, greater dialysis efficiency, less treatment interruptions, and overall, less complications. If it is thought that the patient will require dialysis for greater than 2 weeks, has no active bloodstream infections, and no significant coagulopathy, one may consider initial placement of a tunneled catheter.1

Which modality is best?

RRT manages fluid balance and solute clearance in the setting of AKI through ultrafiltration, convection, and diffusion. Ultrafiltration refers to the movement and removal of plasma water. Convection (hemofiltration) is a form of solute clearance that relies on the movement of water and its dissolved solutes through the semipermeable membrane dragging solutes along. Diffusion (dialysis) relies on the concentration gradient between the blood and the dialysate to remove solute. In diffusion, clearance is inversely proportional to the size of the molecule. Convection more effectively removes medium to large-sized molecules from the blood compared with diffusion.

There are several modes in which RRT can be delivered to critically ill patients. Most often used are intermittent hemodialysis (IHD), continuous renal replacement therapy (CRRT) and prolonged intermittent renal replacement therapy (PIRRT). Peritoneal dialysis (PD) has also been used in the ICU population but is mainly used in limited resource centers or in the pediatric population. The ideal modality should be based on patient parameters including hemodynamics and volume status, metabolic derangements, overall goals of RRT, and local expertise and resources.

CRRT has become the predominant mode within ICUs in the USA. The main rationale for this is CRRT occurs at a lower rate and reduces osmotic shifts decreasing the risk of hemodynamic instability and intradialytic hypotension in critically ill patients. The adoption of CRRT has been facilitated with advances in technology, simplifying modern machines, and educating and incorporating bedside ICU nursing and intensivists to provide therapies in the critical care unit. One major disadvantage of CRRT is that the patient remains connected to the circuit for a prolonged period of time. There are several modes of CRRT including continuous venovenous hemofiltration using convection, continuous venovenous hemodialysis (CVVHD) using diffusion, and continuous venovenous hemodiafiltration using both diffuse and convective modes. These are further described in table 3.

Clinical situations requiring rapid correction of metabolic abnormalities such as severe hyperkalemia and intoxications are better served by IHD. Use of IHD in a hemodynamically unstable patient may be optimized by increasing treatment time, increasing the bath sodium concentration, and decreasing the bath temperature.1 Many patients will transition between modes based on their clinical state. PIRRT finds a balance between the two more commonly used modes. Lower rates mimicking CRRT decrease intradialytic hypotension while providing the patient periods of time free from RRT allowing for procedures, imaging, and increased mobility.

There has been a recent increase in PD use among ICU patients driven by the COVID crisis and resulting strain on resources. This experience led many to reassess the role of PD in critically ill patients. Main advantages include minimal blood loss and less hemodynamic instability versus other modalities. PD is simple to initiate, access can be placed at bedside, and does not require costly equipment.15 Relative contraindications include recent abdominal surgery, abdominal sepsis, and severe respiratory failure continue to limit use in surgical patients. A meta-analysis published in early 2024 demonstrated a possible mortality advantage of PD versus Hemodialysis in AKI; however, there were several limitations to this study.16 Table 4 compares the characteristics of the different RRT modalities.

Several studies have been undertaken to identify advantages between these various RRT options. Currently, there is limited evidence to select one modality over another. Secondary analysis of the STARRT-AKI trial did demonstrate those with initial CRRT had a lower rate of dialysis dependence and greater ICU and hospital-free days at 90 days; however, these patients also had better kidney function at baseline limiting the impact of these results.17 Alternatively, pooled analysis of patients undergoing initial CCRT in the AKIKI and IDEAL-ICU trials was associated with higher mortality at 60 days and no difference in dialysis dependence.18

Once the optimal modality is determined for the patient, an RRT dose must be prescribed. For dialysis, this is conveyed by the function Kt/V, where K is dialyzer clearance, t is duration time of dialysis treatment, and V is volume of distribution of urea.2 The dose of CRRT is conveyed as the effluent dose adjusted for body weight expressed as milliliter per kilogram per hour. Due to common treatment interruptions encountered during CRRT, the delivered dose can be up to 20% less than the prescribed dose. The VA/NIH ARFTN (Acute Renal Failure Trial Network) Multicenter Trial and the RENAL trial both demonstrated no benefit to higher dose therapies. Based on these findings, KDIGO group created recommendations regarding optimal dosing of RRT. Each dose should be individualized for the patient to meet specific goals regarding electrolyte management, acid-base status, solute clearance, and fluid balance. This should be reassessed before each session. The recommended dose for IHD or PIRRT is a Kt/V of 3.9 per week, while for CRRT the recommended effluent volume is 20–25 mL/kg/h, which usually requires a higher prescribed volume.14 Medications and nutrition need to be monitored and adjusted based on RRT modality and dosing.

Special considerations in surgical ICU patients

When to stop RRT

There is limited guidance on when and how to stop RRT in ICU patients. Assessment to stop RRT should occur when there are signs of renal recovery and resolution of the acute illness. The KDIGO group recommends, ‘RRT should be discontinued when it is no longer required, because intrinsic kidney function has recovered to the point that it is adequate to meet the patient’s needs.’16 Clinically, this is often interpreted using variable application of the measures (1) adequate UOP>1000 mL/day or UOP>2000 mL/day in setting of diuretics, (2) spontaneous decrease in serum creatinine, (3) absence of any AKI KDIGO stages and (4) not requiring RRT in the past 7 days.24 ICU patients on CRRT and PIRRT should be transitioned to IHD if they continue to require RRT.

Highlights

• There is a high incidence of AKI in surgical and trauma patients with resulting ↑ morbidity and mortality.

• KDIGO is the preferred definition and classification system for AKI.

• Biomarkers [TIMP2]∙[IGFBP7], NGAL, KIM-1, and GST can be used in Point of Care (POC) setting for early AKI diagnosis and guide therapies which can result in improved outcomes.

• There is NO benefit to early RRT if accepted triggers are not present.

• KDIGO stage 3 AKI does not mandate immediate RRT; however, if no renal recovery is noted after 48–72 hours, initiation of RRT will benefit the patient.

• Many patients with AKI will be spared RRT using the delayed strategy for RRT initiation.

• Use the right internal jugular vein for vascular access. Catheter tip should be in the right atrium.

• There are limited data to support CRRT versus IHD as first mode of RRT, even in unstable patients.

• Patients with intracranial hypertension—TBI, liver failure, stroke, cerebral edema—benefit from CRRT.

• Regional anticoagulation with RCA is ideal for surgical and trauma patients on CRRT.

• Intravenous contrast is safe in patients with AKI. Provide adequate intravenous hydration during pericontrast period.