Acute kidney injury is a very common condition affecting about 5% of non-critically ill and 27% of critically ill children (1, 2). Children who have AKI have longer hospitalizations, prolonged need for mechanical ventilation, higher risk of developing CKD especially in the setting of repeated AKIs, and increased risk of mortality (1–6). The incidence of all causes of CKD as well as CKD after AKI are not well described and is likely underreported due to lack of routine screening (7). CKD is common in the US and it is associated with poor cardiovascular outcomes, anemia, dyslipidemias, altered growth and neurocognition in children which are all associated with poor health outcomes and quality of life in both children and adults (8, 9). AKI has long been recognized as a risk factor for CKD and recent literature has suggested that acute kidney disease (AKD), a term first introduced by the KDIGO group in 2012 and defined as persistent kidney dysfunction beyond 7 days and up to 3 months, may also be an independent risk factor for CKD (10, 11). Recent literature suggests that AKI, AKD, and CKD may be a continuation of the same ongoing disease process rather than separate entities; a graphic representation of this continuum is shown in Figure 1. The trajectory of kidney recovery after AKI and AKD is highly variable and therefore it is important to better understand what factors will increase a child's risk of non-recovery and to identify at risk children early. Studies have shown that children with rapid and sustained reversal of their kidney injury within 48 to 72 h tend to have better outcomes than those with persistent kidney injury irrespective of AKI stage (12–14). Persistent, as well as relapse of reversed kidney injury, is very common in hospitalized patients and is associated with longer hospital and ICU length of stay, need for kidney replacement therapy, and mortality compared to those with early sustained reversal of AKI (6). AKD has been found to be associated with new diagnosis of CKD as well as increased 1-year mortality in adults (15). Both AKI and AKD have been shown to be independent predictors of new CKD diagnosis and by better recognizing which children are at risk for progressing along the AKI-AKD-CKD path, providers can better prognosticate and implement kidney protective measures during this vulnerable period (16–20). Although AKI as a predictor of CKD has been well studied, it is more likely that a combination of injury severity, prolonged injury, and patient level risk factors play a role in progression of AKI to AKD and CKD. Recent discoveries in risk factors for AKI to AKD progression may provide insight into which children are at risk that may benefit from closer monitoring and care by a nephrologist. By better prognosticating which children may progress along this spectrum, nephrologists would better be able to discuss methods to mitigate further kidney injury and promote kidney recovery with families and providers.

AKI has been well studied over the last several decades leading to significant changes in its definition and classification. The RIFLE criteria (Risk, Injury, Failure, Loss of Kidney Function, and End-stage Kidney Disease) were first proposed in 2002 the ADQI (Acute Disease Quality Initiative) group and published in 2004 (21). The RIFLE criteria were adapted for use in pediatrics (pRIFLE) and were able to accurately identify AKI in children (22). These criteria staged kidney injury severity based on serum creatinine, eGFR changes, and urine output and classified patients on two outcomes (loss of function and end-stage kidney disease). Although this criteria was able to identify patients with AKI well and to accurately prognosticate mortality it had limited evaluation in prospective studies (21). In 2005, the AKIN (Acute Kidney Injury Network) Working Group proposed a modification of the RIFLE criteria. The AKIN classification only considers a diagnosis of AKI once dehydration is corrected and urinary obstruction is ruled out. It relies on serum creatinine and urine output measurements over a 48-hour time frame and unlike the RIFLE criteria does not consider the eGFR. Much like the RIFLE criteria, the AKIN criteria was able to accurately identify patients with AKI but it had poor ability to predict in-hospital mortality (21). Most recently, the KDIGO (Kidney Disease Improving Global Outcomes) group proposed in 2007 and published in 2012 a new consensus classification system for AKI with the goal of harmonizing pediatric and adult AKI classifications (23). These definitions are now routinely used in both clinical practice and research. Table 1 shows the different criteria used by the RIFLE, pRIFLE, AKIN, and KDIGO groups for diagnosis of AKI.

AKD is a newer concept in the kidney disease lexicon and was proposed to better define the time period between AKI and CKD. The first concept was first suggested in 2012 and the first suggested definition and staging guidelines for AKD were recommended by the ADQI group in 2017. The ADQI group defined AKD as persistent stage 1 AKI or greater for >/= 7 days and staged it based on degree of serum creatinine increase from baseline (24). This definition was broadened in 2021 by the KDIGO group to include functional criteria for AKI as well as more subtle changes in eGFR and creatinine that may not meet the criteria for diagnosis of AKI (11). AKD can further be classified as AKD with or without AKI which includes those patients who don't meet creatinine or urine output criteria for AKI but do meet criteria for AKD (11, 24). Although no specific staging was presented in the consensus guidelines, it was proposed that AKD could be staged based on severity of eGFR decline as well as albuminuria (11). The ADQI and KDIGO definitions of AKD are outlined in Table 2.

Lastly, CKD is defined as an abnormality of kidney function defined by eGFR <60 ml/min/1.73 m² or abnormal structure or function present for >90 days with implications on future health. Markers of kidney damage can include albuminuria, abnormal urine sediments, electrolyte or other abnormalities suggesting tubular disorder, abnormal kidney histology, abnormal kidney imaging, or history of kidney transplant. CKD, like AKI, is classified into stages by severity of the kidney dysfunction by eGFR and degree of albuminuria originally outlined by the Kidney Disease Outcomes Quality Initiative (KDOQI) group and most recently defined by the KDIGO group [Table 3] (25, 26).

The focus of the remainder of this review will be on the current data on the prevalence of AKD, and the risk factors for AKI-AKD and AKD-CKD progression. The review will also describe the state of knowledge on candidate biomarkers for disease progression following AKI and how we can leverage these biomarkers and clinical factors to identify children that are at risk of disease progression.

AKD is a relatively new concept and there are limited studies on the prevalence of AKD in pediatric populations. Table 4 outlines pediatric and adult studies of AKD epidemiology, risk factors, and outcomes. Pediatric studies in special populations have shown variable incidence of AKD ranging from 6.2% in children undergoing cardiopulmonary bypass, 13% in non-kidney solid organ transplant recipients, 15.6% in children with severe malaria infection, 35.3% in allogeneic hematopoietic stem cell recipients, and 42.3% in hospitalized children with AKI (16, 27–30). Adult studies have shown even more variability with incidence ranging from 3.8% in the general adult population of a single Canadian territory to 4.4%–74% in adults of special populations including those undergoing cardiac and non-cardiac procedure, chemotherapy, hematopoietic stem cell transplant recipients, those with AKI, heart failure, sepsis, cirrhosis, and SARS-CoV-2 infection (20). Hospitalized adults with AKI admitted to both the general floors as well as ICUs had high prevalence of AKD with most studies showing about one-fourth to half of all patients developing AKD (19, 31–40). Adults with cardiac diseases, post cardiac surgery, sepsis and cirrhosis all had high AKD prevalence suggesting hemodynamic status may play a significant role in sustained kidney injury and progression (17, 18, 37–46, 48). The wide variability in prevalence suggests there is a significant role for patient level and hospital acquired risk factors in the development of AKD after AKI.

Risk factors for AKD in children have not been widely studied. Few studies that have been published demonstrated a higher risk of AKD in children with higher stages of AKI with one study showing that stage of AKI predicted AKD in a graded manner (16, 27, 29). Though stage of AKI has been shown to be an important risk factor for progression to AKD, studies in adults and children have shown patient-level and acquired risk factors independently increased risk of AKD independent of AKI stage suggesting that patients with lower stages of AKI also deserve close evaluation for AKD risk. A study of children who have undergone hematopoietic stem cell transplant showed that older age, higher baseline eGFR and higher body mass index (BMI) were associated with increased risk of AKD (28). A study of a more general population of hospitalized children also showed that children with glomerulonephritis compared to other AKI etiologies were at higher risk for developing AKD after AKI suggesting that intrinsic kidney disease may also be an important predictor of progression to AKD (29). Although this is the only study assessing AKI etiology as a risk factor for AKD in pediatrics, a study in adults hospitalized with AKI showed similar results when evaluating intrinsic kidney injury and rates of AKD suggesting that AKI etiology is also an important consideration when evaluating a patient's prognosis for kidney recovery (31).

There have been more comprehensive studies of risk factors for AKD development in adults as outlined in Table 4. In hospitalized adults with AKI, age, gender, intrinsic kidney disease, AKI stage, oliguria, anuria, nephrotoxin exposure, early need for dialysis, BUN level, diabetes, anemia, and respiratory failure have been associated with AKD development (31–33). In adults admitted to an ICU setting age, male sex, African American race, sepsis, lower baseline eGFR and CKD, anemia, and lower ejection fraction have been shown to be risk factors for AKD (35, 39, 45). In the setting of cardiac disease including myocardial infarction, heart failure, and cardiac surgeries, increased risk of AKD was associated with age, female sex, AKI stage, diabetes, baseline CKD, hemoglobin, albumin, BNP, inotrope use, and outpatient loop diuretic use (17, 41, 43, 47). There are several established risk factors for developing AKD in adults undergoing non-cardiac procedures including age, intraoperative hypotension, and coronary artery disease (46, 52). In addition, other risk factors in adults hospitalized with COVID include hypertension, baseline CKD ≥ stage 3, low hemoglobin, low CRP, nephrotoxin exposure, and congestive heart failure have been associated with AKD (53–55). These studies demonstrate that there are some risk factors for AKD that are common to different populations but in general, each special population has its own unique patient-level risks. This highlights the need for comprehensive and large cohort studies to define the risk factors associated with AKD and develop a better understanding of how these risk factors play a role in prolonged kidney injury. No comprehensive studies have been completed yet that have assessed a wide range of patient-level risk factors for AKD in children with AKI.

Outcome studies in both adults and children have shown that AKD and not AKI stage is a significant risk factor for new onset CKD, need for kidney replacement therapy, and mortality further underscoring the importance of understanding patient level risk factors associated with development of CKD following AKI. The variability in AKD epidemiology suggests a significant relationship between AKI stage, patient level pre-existing risk factors, modifiable risk factors including medication exposures and hemodynamic status, as well as etiology of AKI. A risk prediction tool utilizing these different exposure patient-level and iatrogenic criteria may better allow for clinical risk stratification and identification of patients who are likely to develop AKD. This significant variability in prevalence of AKD as well as risk factors is shown in Table 4 and further emphasizes the fact that different clinical tools may be needed for separate populations.

Common biomarkers of AKI including creatinine, cystatin C, and urine output lack the ability for early kidney injury detection. Many other biomarkers have been studied with the goal of early identification of AKI but there have been minimal studies assessing their value as predictive markers for progression of AKD to CKD. A summary of well-studied candidate biomarkers is reviewed here and reviewed in Table 5.

Severe AKI and repeated AKIs have long been known to be a risk factor for CKD but recent literature suggests that AKD may be better predictor for disease progression. Limited studies in children and many studies in adults have shown that risk of AKD is dependent on stage and duration of AKI as well as a myriad of patient level risk factors. AKD itself increases the risk of new onset CKD, progression of CKD, development of ESKD, and mortality. By better understanding which pre-existing and iatrogenic factors place children with AKI at risk for longer duration of kidney injury we can help better prognosticate their likelihood of AKD and CKD after AKI. Early identification of at-risk children can allow for better kidney centered care and avoidance of repeated injuries and factors that promote irreversible kidney injury.

We propose that a combination of a clinical tool which identifies AKD and CKD risk by clinical factors in conjunction with biomarkers of early and prolonged kidney injury would best allow nephrologists to identify children who are at risk for persistent kidney injury. A proposed schematic for biomarker and clinical tool-based care is shown in Figure 2 with suggested follow up, counseling, and monitoring adapted and extrapolated from the recent ADQI meeting report (128). This model has been extrapolated to include monitoring for development of AKD as there are no specific guidelines or models in the literature for this. As shown in this review, there is significant heterogeneity in the risk of kidney disease progression as well as risk factors among both children and adults. In this setting, different clinical tools tailored to individual populations may be more suitable rather than one universal clinical risk prediction tool. We have suggested candidate biomarkers in this article which should be better studied for their ability to predict risk of progression to AKD and CKD. These biomarkers tend to be altered much sooner than classic markers of AKI including serum creatinine, urine output, and cystatin C. Many of these biomarkers have been shown to be persistently elevated long after AKI has resolved underscoring the importance of identifying molecular markers that can reveal subclinical and prolonged kidney dysfunction. There are limited studies that have shown that elevation of these biomarkers in the AKI period may aid in identification of children who are at risk for AKD. Further studies are needed to clarify if early changes in biomarkers can be used in prognostication.

Although it is important to classify AKI by stage, it is also important to recognize that this alone does not explain a child's risk of developing CKD and its sequelae. Other factors must be taken into consideration when assessing the overall morbidity and mortality associated with a single or even repeated episodes of AKI. It may be more appropriate to consider how the child's future kidney health will be affected by their AKI episode and for this we must better understand the other risk factors that promote AKI-AKD-CKD progression. There are no well-studied therapeutic options for preventing kidney disease progression after AKI but by better understanding which children are at risk we may facilitate the study of disease modifying behaviors and therapies. Despite all that is known, more studies are needed for early identification of at-risk children so we may better mitigate adverse outcomes of AKI in this vulnerable population.