Controversies in Pediatric Acute Kidney Injury and Continuous Renal Replacement Therapy

Abstract

Purpose:

Pediatric patients represent a unique challenge for providers managing acute kidney injury (AKI). Critical care for these children requires a precise approach to assessment, diagnostics, and management.

Recent Findings:

Primarily based on observational data, large epidemiologic datasets have demonstrated a strong association between AKI prevalence (1 in 4 critically ill children) and poor patient outcome. Drivers of AKI itself are multifactorial and the causal links between AKI and host injury remain incompletely defined, creating a management paradigm primarily supportive in nature. The previous decades of research have focused primarily on elucidating the population level epidemiologic signal of AKI and use of renal replacement therapy (RRT), but in order to reverse the course of the AKI ‘epidemic’, future decades will require more attention to the individual patient. A patient-level approach to AKI in children will require sophisticated approaches to risk stratification, diagnostics, and targeted utilization of therapies (both supportive and targeted toward drivers of injury).

Summary:

In this review, we will summarize the past, present and future of AKI care in children, discussing the ongoing work and future goals of a personalized approach to AKI medicine.

Introduction

The latter part of the 20^th century and the beginning of the 21^st witnessed a dramatic evolution in the care of critically ill patients. The utilization of not just mechanical ventilation, but a litany of other extracorporeal therapies to support failing organs, continuous medications to support decompensating host physiology, and diagnostics to monitor patients in real-time (including the electronic medical record – EMR), has led to the ability to manage patients previously considered forgone, recognize deteriorating patients before decompensation, and improve the matching between pathophysiology and clinical manifestations of injury. The understanding and management of acute kidney injury (AKI) is emblematic of this evolution. Going from an end-stage, rescue based approach to a more pre-emptive and prophylactic approach to AKI supportive care, critical care providers can now help promote the survival and recovery of patients who decades ago would have otherwise died. Despite the progress, however, significant vertical steps are required to improve outcomes of critically ill patients with AKI. Pediatrics offers a unique paradigm to describe both the evolution of AKI and the needed next steps of care. In this review, we will explain the past and present care paradigms of AKI and renal replacement therapy (RRT) and the future goals using a “SWOT” (Strengths, weaknesses, opportunities, and threats) approach (Figure 1) – with a focus on the goal - a targeted approach to, and personalized medicine for, AKI.

Figure 1. AKI SWOT Analysis.

– The depiction demonstrates the strengths, weaknesses, opportunities, and threats (SWOT) in the current landscape of data and information related to acute kidney injury.

Pediatric Acute Kidney Injury Past and Present – A SWOT Analysis

Strengths:

Pediatric AKI care and research have improved significantly over the past decade, in large part due to the implementation of a consensus definition as part of the Kidney Diseases Improving Global Outcomes (KDIGO) clinical practice guideline.(1) Standardization of these AKI criteria has facilitated improvements in clinical care and has increased the ease with which reliable studies needed to elucidate the epidemiology and outcomes of neonates and children with AKI can be performed. In the time since, large multinational studies have now been published in both critically ill neonatal(2) and pediatric populations(3, 4) which provide definitive evidence of both the high prevalence of AKI in these patients (roughly one in four critically ill children and one in three neonates) and its dire associations. It is now clear that AKI is independently associated with mortality (particularly when severe) and increased resource utilization, including longer lengths of stay, and prolonged mechanical ventilation. Importantly, the relative lack of potentially confounding comorbid conditions in critically ill children compared to adults more clearly suggests a relationship between AKI and these poor outcomes. Taken together, the major strength of pediatric AKI research and clinical care in 2021 is the mandate these data have provided to make the advancement of care for this common and consequential disorder a priority.

Weaknesses:

Unfortunately, despite adoption of a consensus definition and the evidence highlighting its significance, recognition of AKI in pediatric patients remains poor (5–10). This failure to recognize AKI when present results in missed opportunities to provide supportive care interventions, such as monitoring fluid balance, avoiding nephrotoxic medications, and ensuring appropriate diagnostic tests and monitoring. Under recognition of AKI also exacerbates another significant barrier to research: the substantially smaller numbers of patients available for enrollment in pediatric studies. Add to this unique considerations within the pediatric population— such as reluctance to obtain serum samples, difficulty measuring accurate urine output, and lack of consensus guidance for baseline serum creatinine estimation if unknown⁸— and it is clear that a major limitation to advancing AKI care in children is a failure to appropriately recognize injury.

Perhaps more importantly, increasing understanding of the heterogeneity of AKI means that a “one-size fits all” approach to management is unlikely to be successful (11), and thus improving care for these patients hinges on improvement in diagnostic precision beyond the current standards of serum creatinine elevation and decreased urine output. A more precise diagnostic framework is a key first step to addressing additional areas of weakness, which include (but are not limited to) a lack of validated pediatric-specific AKI prevention strategies (i.e., AKI bundles) that have shown promise in some adult populations (12, 13), the lack of disease-modifying therapeutic options once present, and a lack of clarity surrounding the optimal timing of RRT initiation and variable acceptance of fluid overload as an indication (14–18).

Opportunities:

These data can and should be used by clinicians and researchers alike to put pressure on the scientific community for increased funding and resources directed towards improving its care and recognition. Encouragingly, recent work has demonstrated that even simple interventions, such as provider education about AKI and increased nephrology presence, have the ability to improve patient outcomes and decrease the incidence of AKI. Additionally, pediatric AKI researchers should leverage the aforementioned pediatric-specific difficulties to inspire innovation. For example, the inherently smaller size of the patient population should encourage enhanced collaboration amongst researchers, while also highlighting the need for a thoughtful, precision medicine approach to patient enrollment (i.e., enrolling only high-risk patients likely to see a benefit from treatment, if one is present) in future interventional studies.

Threats:

Arguably the single largest threat to advancing pediatric AKI care and research is the failure of bedside providers and funding agencies to recognize its clinical importance. While many pediatric nephrologists and clinicians in other specialties that study pediatric AKI understand its aforementioned significance and associated sequelae, the vast majority of those caring for children at risk for and with AKI, as well as those distributing research funding, are not as well versed. This was highlighted recently in the neonatal intensive care unit, where the AWAKEN study demonstrated wide variability in the frequency with which serum creatinine is even measured in critically ill neonates, likely secondary to an under appreciation of the significance of AKI in this population. Ultimately, these knowledge gaps often lead to provider apathy and fatalism surrounding AKI, as it is often seen as an unavoidable and insignificant consequence of critical illness, instead of an entity worth preventing and mitigating to improve outcomes.

The Evolution of Pediatric Renal Replacement Therapy

The use of RRT has been integrated into the care of the critically ill child with AKI. The most common form of RRT in developing countries is peritoneal dialysis with a significant cost and resource advantage when compared to hemodialysis or hemofiltration(19). Since its initial use more than forty years ago, the application of CRRT has evolved from a largely palliative therapy to the mainstay treatment for pediatric (AKI) in developed nations (20, 21). Data from the Prospective Pediatric CRRT (ppCRRT), a North American multi-center registry including data form 13 centers, has been paramount in establishing CRRT as a therapy for children with AKI (14).

Although we do not have data from randomized trials to define the optimal CRRT prescription in pediatrics, we do have expert opinion. In children receiving CRRT a mean blood flow rate of 96.9 ml/min, scaled to 5 ml/kg/min (3–10 ml/kg/min), is generally recommended with higher blood flow rates frequently needed in neonates and infants (22). Studies evaluating CRRT effluent rate and survival in adults have shown no significant difference when the dosage is greater than 20–25 ml/kg/hr (23, 24). Clearances of 2 liters/hour/1.73 m² of BSA are generally accepted in pediatric CRRT (25). The options for anticoagulation for children receiving CRRT have grown over the last two decades. Available anticoagulation options include heparin, citrate, argatroban, prostacyclin or no anticoagulation. Study results have suggested that citrate may be superior to heparin and can be used safely in children with liver failure (26–28).

CRRT in 2021: Gaps in Knowledge

There are clear opportunities to personalize our approach to providing CRRT for children. The use of biomarkers holds great promise in identifying children that are unlikely to show AKI recovery and require RRT initiation. Additionally, refinement of prognostic tools and biomarkers to optimally determine timing for the initiation and discontinuation of RRT is needed. Data from studies on adults exploring the timing of RRT is mixed in showing benefit to the earlier initiation of RRT (29–31). Variability in the definition of “early”, “delayed”, or “late” have added to the challenges for clinicians trying to make conclusions from the literature and has created uncertainty (32) (33).

Importantly, there is much work to be done in optimizing nutritional intake for growing children receiving CRRT. As part of the ppCRRT registry, Zappitelli and colleagues showed that once on CRRT children may continue to receive inadequate protein intake (34). The loss of trace elements and vitamins in the effluent are not routinely monitored (35). Furthermore, there is limited published work regarding the dosage considerations and clearance of medications in children receiving CRRT.

Data from the Assessment of Worldwide Acute Kidney Epidemiology in Neonates (AWAKEN) cohort, including 24 centers worldwide, has shown the association of AKI with mortality and length of hospital stay in neonates (2). After implementation of increased nephrology presence on rounds and dedicated AKI education in the neonatal intensive care unit, investigators at the University of Washington reported a significant decrease in the incidence of neonatal AKI (36). These study results indicate that collaboration between nephrologists and neonatologists is paramount to filling knowledge gaps in the optimal management of RRT in neonates with AKI. The provision of CRRT to neonates is now increasingly described. Faced with the difficulty of delivering effective therapy with the relatively large extracorporeal blood volumes of standard dialysis machines, protocols and recommendations for safely priming CRRT circuits with blood have been published (37). Askenazi and colleagues have reported on the use of the Aquadex Flexflow machine to provide continuous venovenous hemofiltration with the use of a 33 ml total extracorporeal volume.(38) Developed in England, the Newcastle Infant Dialysis and Ultrafiltration System (NIDUS) system, provides dialytic clearance with an extracorporeal volume of < 10 ml.(39) The Cardio-Renal Pediatric Dialysis Emergency Machine (CARPEDIEM) which can provide both convective and diffuse clearance has been approved by the FDA for children up to 5–8 kg (40). Recently, the use of the Prismaflex™ HF20 filter set (extracorporeal blood volume of 60 ml) has been shown to be an effective and safe alternative to larger filter sets for patients weighing less than 20 kg (41).

Moving Care for Pediatric Acute Kidney Injury Forward: A Precision Medicine Approach

The continued advancement of the field of pediatric AKI relies on a commitment to the adoption of a precision medicine approach to its prediction, detection, and management. A schematic of this approach using both current and theoretical examples is outlined in Figure 1. Generally speaking, precision medicine utilizes the concepts of prognostic enrichment (i.e. identification of patients with a higher likelihood of having an outcome of interest) and predictive enrichment (i.e. identification of patients more likely to respond to a specific therapy based on biologic mechanism) in concert to aid in the study and management of heterogeneous diseases such as AKI (42, 43). Goals for the future of pediatric AKI research and clinical care within this framework are outlined below.

Precision Diagnostics:

A dynamic, multi-biomarker approach to the diagnosis of AKI is required. Although urine output and serum creatinine can be helpful indicators of glomerular filtration and maintenance of homeostasis, injury biomarkers need to be validated and integrated into clinical use to elucidate if and where tubular injury has occurred. Additionally, the temporal trends in these biomarkers are likely to be important to elucidate different AKI phenotypes with unique prognostic and therapeutic implications.

Risk Stratification:

Once a more precise diagnostic framework for AKI has been delineated, AKI risk stratification can become more effective and standardized. Unique risk prediction (i.e. prognostic enrichment) tools are required for different patient populations (i.e., those with sepsis, those post-cardiopulmonary bypass, and neonates), and should be employed automatically within the electronic health record (EHR). This risk stratification should be used to inform clinical care, and to identify high risk patients for enrollment in clinical trials seeking to identify novel therapeutics (Figure 2).

Figure 2. A Precision Medicine Approach to Pediatric Acute Kidney Injury Management.

A heterogeneous population of children admitted with or at risk for acute kidney injury are further stratified using both prognostic enrichment strategies (i.e. to identify those at higher likelihood of having an outcome of interest, such as persistent, severe AKI) and predictive enrichment strategies (i.e., to identify different subsets of patients more likely to respond to a therapy based on biologic mechanism), often in concert. Patients deemed to be high risk and/or those identified as having a specific AKI phenotype are then provided with appropriately tailored patient-specific therapy.

Precision Therapeutics:

The routine clinical use of validated tubular injury biomarkers for precision diagnostics will facilitate the identification and study of different AKI phenotypes, allowing for the development and clinical testing of phenotype- and biology-specific therapies (i.e. predictive enrichment). Additionally, improvements in minimally invasive kidney biopsy techniques could allow for identification of histologic and molecular correlates to these phenotypes, which may aid in the discovery of additional novel therapeutics. Overall, the reduction in AKI heterogeneity achieved via development and employment of precision diagnostics and risk stratification techniques will lead to delivery of the right therapy to the right patient, achieving the overarching goal of precision medicine.

The Path Forward in Pediatric Continuous Renal Replacement Therapy

The use of clinical prediction tools such as the renal angina index to identify patients most likely to benefit from CRRT early in their ICU stay is compelling. The role of novel biomarkers to determine the optimal timing for the initiation and discontinuation of CRRT is being explored.(44) Work is being done to standardize the already commonly used clinical practice of using a “diuretic challenge” to determine the need for RRT. The use of the furosemide stress test shows promise for identifying patients for RRT initiation (45).

The 17^th Acute Dialysis Quality Initiative Consensus Conference advocated for adapting a personalized patient’s CRRT treatment to the evolving clinical status to the patient (46). It can be argued that the call to personalized treatment for CRRT is more urgent in children when compared to adults given the greater variability in the size of children. We look forward to the use of better measures of clearance during CRRT therapy using technology such as online sensors that sense changes in not only urea nitrogen, but other molecules (47). Given the known negative effects of fluid overload, there is a critical need to know how much fluid to remove during CRRT therapy and how quickly to remove it. Future investigations on monitoring technology during net ultrafiltration, such as bioimpedance and peripheral intravenous analysis in children receiving CRRT may improve our ability to allow for kidney recovery while not impacting hemodynamic balance (48, 49). It is intriguing to think of dosing CRRT using a real time glomerular filtration rate (GFR) and adjust clearance rates to maintain a GFR between 100–120 ml/min per 1.73m² (14, 50). The use of real time GFR measurements and novel biomarkers to predict renal recovery and ultimately taper and stop CRRT shows great promise. Figure 3 depicts important goals to consider over the following decades regarding delineation of optimal CRRT initiation, monitoring during therapy, and discontinuation.

Figure 3. A Personalized Pediatric Approach to RRT.

There is a need for the universal application of a personalized approach in the decision to initiate continuous renal replacement therapy, deliver optimal therapy, and discontinue treatment at the time of renal recovery in children. Research efforts aimed at exploring the use of predictive tools, novel biomarkers, monitoring of clearance/fluid removal, and real time GFR show great promise for fulfilling this critical need.

Conclusion

Pediatric care is, by definition, pro-active, prophylactic, protective, preventative, and personalized. In this review, we have delineated the current understanding of AKI and RRT in children and discussed the needed work of the future. Pediatricians are, by definition, preventative medicine specialists (e.g., vaccinations, helmets, car seats) and the precision medicine future needed to improve outcomes for children with AKI requires a biomarker integrated, individual approach to regulation of injury, fluid, and delivery of renal replacement. In this way, the goals of care will be protective and preventative, targeted to incipient injury, mitigative of ongoing damage, and restorative to previous health.

Key Points.

• AKI awareness and use of RRT in critically ill children has expanded

• Current diagnostic and management strategies are imprecise

• Next steps for improving pediatric patient care revolve around a precision medicine approach

• Risk stratification and biomarkers may enable a targeted approach to AKI/RRT