Timing Of Kidney Support Therapy in AKI
Dec 30, 2022
The optimal timing of renal supportive care in critically ill patients with acute kidney injury (AKI) without AKI-related life-threatening complications is controversial. Recent multicentre, randomized, controlled studies have questioned the need for early initiation of treatment, although one study showed a survival benefit for early initiation of renal support therapy, whereas others showed no difference in mortality based on the timing of initiation of renal support therapy. These findings reflect uncertainty in the decision to initiate renal supportive therapy, which should ideally be individualized based on the patient's comorbidities, disease severity, renal function trajectory, urine output, and needs for fluid balance and solute clearance. In addition to saving health resources, a delayed approach may also reduce the burden of dialysis dependence. However, we must determine what the waiting period is and the benefits and risks associated with this approach. This article reviews the concept of dialysis timing in AKI, critically evaluates the most important clinical trials on this topic, discusses ongoing research and knowledge gaps, and defines key future research questions that need to be addressed.
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Acute kidney injury (AKI) is common and is associated with an increased risk of chronic kidney disease (CKD), renal failure, congestive heart failure, coronary events, sepsis, stroke, bleeding, and mortality. The annual incidence of AKI is 2,000-3,000/1 million, of which 200-300 will receive dialysis. The incidence of short-term dialysis is highest in critically ill, septic patients, and patients undergoing cardiovascular surgery, with a trend toward increased use of dialysis in critically ill patients.
In patients who are refractory to medical therapy and have life-threatening indications (eg, hyperkalemia, metabolic acidosis, uremic complications, volume overload), prompt initiation of dialysis is warranted. Despite these indications, the timing of dialysis initiation varies widely in clinical practice. Dialysis should be considered as renal support therapy (KST) because it removes uremic toxins, corrects electrolyte and acid-base disturbances, achieves fluid balance to facilitate nutrient or drug administration, modulates cytokine levels in inflammatory states, and is considered to incorporate a multi-organ support platform to limit damage associated with organ interactions. However, these considerations must include exposing the patient to complications associated with vascular access and dialysis, including biocompatibility issues. Over the past 10 years, debates for and against the specific timing of KST have resulted in various clinical practice guidelines, but their recommendations have been inconsistent except for emergency indications.
Considerations for Initiating KST Therapy in Patients with AKI
absolute indication
• Symptoms or signs of uremia (pericarditis, encephalopathy)
• Refractory pulmonary edema (diuretic resistance)
• Refractory hyperkalemia (potassium >6.5 mmol/L or rapid increase or associated with arrhythmia)
• Refractory metabolic acidosis (pH<7.2)
relative indications
• AKI/fluid overload with associated organ dysfunction impact present or expected
• Requires substantial fluid administration (ie, nutritional support, drugs, or blood products)
• Solute burden (ie, tumor lysis syndrome, rhabdomyolysis, intravascular hemolysis)
• Unfavorable evolution of clinical parameters/severe AKI or anuria, low probability of rapid renal recovery
relative contraindications
• Not effective considering overall prognosis (palliative care, limited survival regardless of KST)
• High likelihood of dialysis dependence if long-term dialysis is unacceptable
KST risk
• Complications related to vascular access, including the risk of catheter infection and thrombosis
• Bleeding associated with anticoagulation or heparin-induced thrombocytopenia
• Potential risk of hemodynamic instability and long-term deterioration of renal function
• Removal of drugs/water-soluble vitamins/trace elements/electrolytes
• Biocompatibility issues
• Immobilized events and limited physical therapy in favor of muscle wasting and thrombosis
other factors
• Availability of equipment and personnel
• Patient and family preferences/overall goals of treatment
•Medical expenses
Abbreviations: AKI, acute kidney injury; KST, renal supportive therapy.
Summary of recent and ongoing randomized controlled trials
In the past 5 years, 6 randomized controlled trials (RCTs) have been published to determine the optimal timing of starting KST (Table 2). According to the severity of AKI, KDIGO stage, and AKI-related complications, early or delayed initiation of KST was selected. The ELAIN study showed a survival benefit in early KST compared with late KST, whereas the AKIKI, IDEAL-ICU, FST, and STARRT-AKI RCTs did not replicate these findings. More recently, the AKIKI2 trial showed that delayed treatment was associated with poorer outcomes.
The ELAIN trial was a single-center RCT in patients undergoing cardiac surgery to determine the effectiveness of early KST (8 hours after KDIGO stage 2 AKI) compared with delayed KST initiated within 12 hours of stage 3 AKI for urgent indications or start within) can improve patient survival (Table 2). Plasma neutrophil gelatinase-associated lipocalin (NGAL) > 150 ng/mL, and one of the following: severe sepsis, use of vasopressors, refractory fluid overload (defined as worsening pulmonary edema, PaO2/FiO2<300 mm Hg or fluid balance>10% body weight) or the occurrence/progression of non-renal organ dysfunction (Sequential Organ Failure Assessment [Sequential Organ Failure Assessment, SOFA] score ≥ 2 points). The trial enrolled 231 patients with a mean SOFA score of 16. All patients in the early group received KST compared with 91% in the delayed group. Early KST intervention showed a 15% absolute reduction in 90-day mortality (39% vs 55%; P = 0.03) and a higher rate of 90-day renal recovery (54% vs 39%, P = 0.02). Of note, the ELAIN trial had a fragility index of 3, meaning that 3 more deaths in the early group or 3 fewer deaths in the delayed group would make the outcome a nonsignificant outcome. It is not uncommon for the results of a single-center RCT to be inconsistent with those of a subsequent multicenter RCT. Single-center RCTs are known to report higher efficacy than multicenter RCTs and have more limited external validity. With the addition of NGAL as an inclusion criterion, only 3 patients with plasma NGAL<50 ng/mL were excluded out of 373 eligible patients.
The first large multicenter RCT AKIKI trial included 620 critically ill patients (mainly sepsis patients) receiving mechanical ventilation and/or vasoactive drug support in 31 centers in France (Table 2), with a SOFA score of (11±3 ) Minutes. Compared with ELAIN, patients in the early group received KST not earlier, and patients in the standard group started within 6 hours after reaching AKI stage 3. The late group started KST only when urgent indications were met. The trial was designed to detect an absolute reduction in mortality in critically ill patients of 15%, which is very rare in modern clinical practice to be achieved with just one intervention. Mortality at 60 days was similar: 49 percent in the early treatment group and 50 percent in the late-treatment group. Notably, 49% of patients in the advanced group had never received KST. Dialysis dependence at 60 days was similar in both groups.
The IDEAL-ICU RCT was a 29-center study in France that enrolled 477 critically ill patients with early septic shock and AKI (Table 2). Early KST was defined as starting KST within 12 hours after KDIGO stage 3 AKI and delayed KST was defined as starting KST at least 48 hours after KDIGO stage 3 AKI unless there was an absolute indication. The SOFA score was (12±3) points. At the planned interim analysis, the primary endpoint of 90-day mortality was comparable between the early (58%) and late (54%) cohorts, and the study was terminated for futility. Thirty-eight percent of patients in the advanced group never underwent KST, 8% of them died before KST, and 29% of patients recovered enough renal function to avoid KST.
More recently, STARRT-AKI enrolled more than 2,900 critically ill patients with AKI KDIGO stage 2 or higher AKI from 15 countries (Table 2). This study compared an early KST strategy (KST within 12 hours of meeting inclusion criteria) with a standard KST strategy (delayed KST unless AKI persisted for at least 72 hours or traditional conditions (serum potassium ≥6.0 mmol/L, pH ≤7.20, or serum bicarbonate ≤12 mmol/L, PaO2/FiO2 ratio ≤200 defined as severe respiratory failure, and clinical sensory volume overload). The aim was to improve 90-day survival by 6% absolute. Key secondary outcomes include a composite of death or dialysis dependence; and a major adverse renal event (MAKE) at 90 days. Patients with advanced CKD (estimated glomerular filtration rate [eGFR] <20 mL/min/1.73 m2), rare Etiological AKI, requiring emergency dialysis, or kidney transplant recipients were excluded. Patients who were considered by the attending physician to require urgent KST or should be postponed were also excluded. Thus, of the 11,852 eligible patients, 67% were excluded, leaving 3,019 Patients included in the study, 2,927 of whom were included in the modified intention-to-treat analysis. It is unclear whether the characteristics of the included patients were different from those of the excluded patients, and for these patients, KST was started immediately or could be delayed.
The average SOFA score in the STARRT-AKI group was (12±4), oliguria accounted for 45%, and the weight-adjusted percent fluid overload (%FO) was 3%. Similar to other trials, 38% of patients in the advanced group had never received KST. The time from enrolment to the start of KST was 6 hours in the early treatment group, and 31 hours in the late treatment group. Two-thirds of patients in the advanced group started dialysis for conventional indications, 24% for AKI lasting more than 72 hours, and 10% for unknown reasons. The primary outcome, 90-day mortality, was the same in both groups (44%). Serious adverse events were reported in 0.8% of patients. More adverse events were reported in the early group (23% vs 17%; relative risk [RR], 1.40 [95% CI, 1.21-1.62]), mainly due to KST-associated hypotension (8.7% early vs 5.6% late ) and hypophosphatemia (early 7.5% vs late 4.2%). The 90-day dialysis dependence rate in the early group was higher than that in the early group (10.4%vs6.0%; RR, 1.74 [95% CI, 1.24 ~ 2.43]), and the risk of rehospitalization was also increased (RR, 1.23 [95% CI, 1.02 ~ 1.49] ]). A meta-analysis previously published in STARRT-AKI also found a higher risk of hypotension in early KST.
The FST trial was a multicenter pilot study to determine (1) whether the FST could be used as a screening tool in patients at high risk for KST, and (2) the feasibility of using the FST in a KST timing trial. By definition, FST consisted of 1 mg/kg intravenous furosemide for naive patients and 1.5 mg/kg intravenous furosemide for prior furosemide users. Non-responsive patients were defined as having urine output < 200 mL within 2 hours. In the FST trial, 118 non-responding patients were randomly assigned to receive early treatment, start treatment within 6 hours, or standard KST. In the early-stage group, 98 percent of patients received KST compared with 75 percent in the standard group. There was no significant difference in the 28-day mortality rate (62% vs 58%, P = 0.68) and 28-day KST dependence rate between the two groups.
Finally, the multicenter AKIKI-2 RCT further evaluated the effect of extending the time to start KST based on the AKIKI trial. They enrolled 278 patients in France who were randomly assigned to start KST within 12 hours, indicated by urea >40 mmol/L and/or oliguria >72 hours. Delayed initiation of KST if one or more of the following criteria are present: urea >50 mmol/L, marked hyperkalemia or acidosis, or refractory lung disease due to severe hypoxemia due to fluid overload Edema. Although fewer patients in the delayed group received KST, the primary outcome (number of days without KST 28 days after randomization) was similar in the two groups. There was no difference in crude mortality between the two groups. However, a prespecified multivariate analysis showed higher 60-day mortality despite similar complication rates or length of hospital stay with the delayed strategy. These results do not imply that serum urea nitrogen >50 mmol/L is causally associated with increased mortality.
What can we learn from these randomized controlled trials?
Most studies defined the start time of KST based on the AKI stage, including changes in serum creatinine with or without urine output, relative to the time of onset of AKI, or conventional indications for KST. However, based on the results of recent trials, this traditional concept of KST initiation time may need to be revised. Fluid overload is usually the primary factor initiating KST. However, the percentage of fluid overload adjusted for body weight (3% vs 7% in the STARRT-AKI study) was much lower than in previous observational studies (which could reach 20%). These findings may reflect the evolution of clinical practice over the years since the publication of observational studies such as %FO. In START-AKI, waiting until %FO reached 7% to start KST was no more harmful than starting KST when %FO was 3%. Patients with a severe %FO may be excluded from the study. We cannot conclude from these findings that waiting for %FO to reach 20% is acceptable. Because the kidneys are encapsulated organs, they are more prone to organ congestion and fluid overload. Patients undergoing cardiac surgery or with congestive heart failure may represent the clinical phenotype of patients who would benefit more from early renal support and optimized fluid management. Subgroup analyzes of previous randomized controlled trials including patients undergoing cardiac surgery and congestive heart failure may clarify these issues.
In clinical practice, some patients in the ELAIN, AKIKI, or IDEAL-ICU trials may not have been considered to benefit from KST. The results of the STARRT-AKI study highlight that there is currently no tool to predict the need for or avoidance of KST in patients with clinically balanced severe AKI. Clinical homogeneity was used to guide whether patients met the inclusion criteria, not the time interval after patients reached the criteria for severe AKI. The principle of clinical balance of power excluded patients who were judged by clinicians to be suitable for emergency KST or whose renal function might be about to recover (Table 2). In the STARRT-AKI RCT, 1/3 of eligible patients were considered uncertain about the benefit of KST and were included in the study after obtaining informed consent. In the advanced treatment group, 25% of patients had to start treatment within 19 hours, and 24% could delay it to 72 hours or even longer. These findings suggest that a more dynamic approach is needed to quantify KST demand and wait for risks as well as daily KST-related risks. As shown in the subgroup analysis of sepsis patients in STARRT-AKI and a previous meta-analysis, the prognosis of medical critically ill patients is more dependent on underlying diseases such as septic shock, and thus may not benefit from early KST.
A meta-analysis published before STARRT-AKI by Gaudry et al reported that delay in initiation of treatment was associated with no difference in mortality and was consistent with sensitivity across different subgroups (age, sex, disease severity, sepsis, and CKD). Across the analyses, these results were unchanged. These findings suggest that delaying KST as much as possible may lead to a substantial reduction in the percentage of patients who ultimately undergo KST. However, we need to better understand why these patients can avoid KST. These reasons were not adequately accounted for in any of the trials. In the STARRT-AKI trial, the authors reported that 12.5% of patients died before KST. Understanding the clinical characteristics and prognosis of patients without KST is of great significance to guide clinicians to improve patient management. For example, whether urine output and %FO differed in the late-stage group of patients who received or did not receive KST, and whether FST-isofurosemic stress could predict this need. This may also include baseline characteristics as well as the course and general status of renal function. Results from the BICAR-ICU RCT suggest that bicarbonate therapy may avoid KST in patients with severe metabolic acidosis and AKI, in addition to optimizing patient outcomes, and it is unclear whether these findings apply to recent RCTs.
Long-term renal function after KST is an important indicator to evaluate the therapeutic effect. Observational trials have found that underlying CKD, incomplete renal recovery or the presence of proteinuria predicts poorer renal outcomes. Significantly more patients with CKD were enrolled in the STARRT-AKI trial than in previous studies (44 percent compared with 10 percent in the AKIKI trial and 16 percent in the IDEAL-ICU trial) (Table 2). In a meta-analysis published before this RCT, no significant between-group differences were found in KST dependence at discharge, nor in serum creatinine levels at the same time points, however, the quality of the evidence was low. In a meta-analysis including STARRT-AKI, early initiation of KST increased the risk of dialysis dependence in the subgroup of patients who were not on continuous dialysis and had a SOFA score above 11. Notably, the included studies were highly heterogeneous and prone to bias.
Information on the causes of death in patients who did not receive KST will help determine whether the provision of KST can modify these circumstances. For example, oliguria and higher %FO at the initiation of KST were associated with poorer outcomes in observational studies. In STARRT-AKI, median urine volume at the initiation of KST was lower (350 mL vs 453 mL) and fluid overload was more common (6.7% vs 3.1%) in the late group compared with the early group, but these findings did not change the overall outcome.
While waiting for dialysis was associated with a lower incidence of KST, patients received KST longer and had a longer ICU stay. In addition, these patients require heavy use of diuretics and drugs to control fluid overload, hyperkalemia, and acidosis. Sodium polystyrene sulfonate is often used to treat hyperkalemia in the absence of other treatments. However, there are concerns that the drug may promote intestinal necrosis, especially in postoperative patients and in patients with ileus, obstruction, or bowel disease. In addition, the effect of drug utilization on overall resource allocation was not described.
How should we update current guidance?
A key issue in the optimal timing of KST is balancing the risks of unnecessary surgery with the need for vascular access and the potential failure to address potentially treatable diseases over time. These concepts were considered differently in these trials, as they focused on identifying harms associated with treatment complications and the effect of early initiation of treatment on outcomes. However, it is equally important that we need to consider the risks of a long wait, as a delay in starting treatment may lead to irreversible disease, making it less likely to benefit from KST.
We have previously shown that delayed treatment of severe AKI leads to an increased risk of organ failure and fluid overload associated with higher mortality. Results from the AKIKI2 trial also support these findings. In addition, complications related to the severity of the underlying disease have been shown to correspond to higher attributable risks of death. Therefore, we need to have specific criteria to determine the outer boundaries of waiting for delayed intervention.
For patients with urgent KST indications, the expected benefits generally outweigh the potential risks if related to patient preference and overall prognosis (Figure 1). For patients with relative indications for starting KST, the expected benefits and potential risks should be evaluated, and the treatment preferences of patients or family members must be considered when making decisions. These should form part of a shared decision with the patient and their surrogate when deciding whether to initiate a KST, especially before urgent indications are met. RCTs on the duration of KST treatment included only intermittent hemodialysis and continuous renal replacement therapy (Table 2). During the recent COVID-19 pandemic, some medical centers relied on emergency initiation of peritoneal dialysis to save lives due to resource constraints. Therefore, logistical aspects such as the availability of staff, machinery, and disposables should also be considered in the decision-making process.
What should be done next?
We must rethink our approach to studying the timing of KST, which is largely driven by oliguria due to AKI severity and complications based on serum creatinine criteria. The ADQI recently made recommendations on AKI biomarkers, emphasizing the need for further research on a dynamic assessment of kidney injury and functional biomarkers in clinical data to determine the optimal timing of KST. We need a clear understanding of the parameters used to define the waiting period, its duration, and the best way to implement targeted therapy to manage complications of hyperkalemia, acidosis, and fluid overload. The number and duration of complications are associated with adverse outcomes, so we must refine the risks associated with the waiting period to individualize patient management.
We need dynamic, quantifiable measurements to determine individual patient trajectories. Small studies have found that, for the majority of patients, FST predicts which patients are likely to progress to more severe AKI and require KST. In the FST trial, 86% of responding patients avoided KST, whereas 75% of nonresponding patients eventually required KST. In another study, FST outperformed common AKI biomarkers in predicting the need for KST in early AKI. As far as we know, 4 models have been built to predict the demand for KST. The period used to evaluate the model ranged from the next 48 hours to the total hospital admission, with good predictions (area under the curve, 0.82 to 0.96). These models should be validated prospectively in other cohorts.
Another approach currently being evaluated is to calculate the degree of mismatch between the demand on the kidney and its capacity. The method includes an assessment of disease severity, fluid balance, AKI severity, and urine output at a given time point, and provides a dynamic score to predict a patient's disease course. Clinicians can carry out individualized treatment according to the changing trend of the mismatch score, distinguish which patients may need KST more or less, and benefit from it. Clinicians have the option of initiating KST if a patient experiences progressively increased need and decreased capacity, or waitlisting for patients with improved disease severity and renal function. This comprehensive approach reinforces current clinical practice, where current KSTs are often based on fluid balance and disease severity with expected trends in AKI worsening and decreased urine output. The patient's comorbidities, as well as the risks and potential harms of surgery compared to the risks of waiting, can also be considered. The approach needs to be further defined by objective measures and tested in clinical trials to see if it is associated with improved outcomes and reduced resource use.
In conclusion, the decision to initiate KST is usually individualized, based on the patient's comorbidities, disease severity, renal function and urine output trajectory, and requirements for fluid balance and solute clearance. The clinical judgment of whether or not to initiate KST can be supplemented with other tools for risk stratification, such as needs-capacity mismatch concepts, renal injury and functional biomarkers, and FST, to provide more timely interventions and improve outcomes. Delaying treatment may reduce the burden of dialysis dependence or reduce health resource utilization. However, we must determine what the waiting period is and the benefits and risks associated with this approach. We need more research in this area to inform the individualized management of patients while understanding changes in practice.
for more information:Ali.ma@wecistanche.com
