Stop adding insult to injury—identifying and managing risk factors for the progression of acute kidney injury in children

Children have the potential to recover ostensibly normal kidney function following an episode of AKI, however a growing body of evidence suggests that chronic sequelae may be under-recognized. Over one-third of 176 children treated for AKI at a U.S. tertiary center had reduced kidney function, or remained dialysis dependent, at the time of discharge from hospital [8]. In the 3- to 5-year follow-up of this cohort, 17 of 29 children had long-term effects, including hyperfiltration, reduced kidney function, hypertension or proteinuria [9]. In another follow-up study of 126 children treated in intensive care, 10% had CKD within 1–3 years following AKI [10]. A U.S. study of 63 pediatric heart transplant recipients with AKI showed that 5% of the patients had developed CKD at 12-month follow-up [11], and six of 37 children treated for AKI at a tertiary center in India had abnormal renal parameters at 10-year follow-up [12]. Infants who experience AKI in the neonatal period have an increased risk of abnormalities in kidney function in the long term [13, 14]. Taken together, these data demonstrate that recovery of normal kidney function following AKI in children is by no means guaranteed; pediatric AKI cannot be treated as an isolated event without due attention paid to the potential consequences.

Some children do recover their baseline kidney function following AKI, however understanding functional renal recovery in children is challenging for a number of reasons. Firstly, pediatric follow-up studies to date have not applied a standard definition of renal recovery, with definitions varying from dialysis independence during a hospital stay through to normalization of plasma creatinine, blood pressure and proteinuria. Secondly, the natural history of increasing glomerular filtration rate (GFR) in the first year of life from 15 to 90 ml/min/1.73 m² presents challenges in defining baseline kidney function for infants. Thirdly, children have substantial renal reserve, so significant kidney damage resulting from an AKI episode can be compensated by hyperfiltration and may therefore not be reflected in the plasma creatinine level until adolescence or adulthood [15]. These challenges highlight the need to look beyond an operationalized definition of renal recovery based on functional measures, such as creatinine, in order to identify children who are at greatest risk of long-term sequelae following AKI. The identification of such children requires a deeper understanding of the sequence of events that follow an acute kidney insult, namely injury, repair and potential progression.

Until recently, progress in characterizing the events that follow an acute kidney insult was hampered by the lack of a consensus definition of progression and its associated events. Following recognition of this issue, a working group of the 13th Acute Dialysis Quality Initiative (ADQI) Conference sought to clarify these concepts. This group outlined a paradigm for understanding the clinical course of AKI and proposed definitions for terms related to events mediating resolution or progression [16]. They conceptualized the events that follow an acute kidney insult in three phases, as illustrated in Fig. 1. The development phase represents the immediate effects of the initial insult, which may be subclinical. The extension phase then ensues, in which both injury from the kidney insult and repair mechanisms compete. The resolution phase represents the net outcome of damage and repair. The duration of each phase can vary considerably depending on the nature of both the kidney insult and repair processes.

Concepts relating to progression following AKI are best understood in the context of the sequence of events described above. In the development phase, a kidney insult leads to injury. In the extension phase, repair processes are initiated in response to injury. Adaptive repair is a coordinated process, resulting in the resolution of renal structure without long-term sequelae. In contrast, maladaptive repair results in durable reduction in kidney function usually associated with a change in renal structure. The extension phase represents the net result of renal injury and repair processes. Renal recovery is a consequence of adaptive repair that leads to durable improvement in kidney function or structure. Conversely, progression is defined as a durable change in kidney structure or function detected by biomarkers, imaging studies or histopathology [16].

Recent progress has been made in operationalizing a definition of renal recovery; the Kidney Disease: Improving Global Outcomes (KDIGO) AKI work group developed the entity “acute kidney disease” to characterize partial functional recovery following AKI [5]. This was defined as a GFR of <60 ml/min/1.73 m² or evidence of structural kidney damage for less than 3 months. This concept bridges the gap between the “Loss” and “End Stage” categories of the pediatric RIFLE criteria [17]. In clinical practice, recovery is often thought of as a return to baseline plasma creatinine. As discussed above, functional renal recovery should be interpreted with caution in children, as a return to baseline creatinine may mask underlying durable kidney damage.

There is a growing understanding of the pathophysiologic mechanisms that underlie progression following AKI. Acute kidney insults disrupt tubules, capillaries and glomeruli, with the proximal tubule being particularly vulnerable [18]. Repair processes are then initiated in response to the insult [19, 20]. Sustained recovery can be attributed to adaptive repair processes resulting from a well-balanced response between inflammatory and anti-inflammatory factors [21]. In many situations, this fine balance is not achieved, resulting in maladaptive repair, which predisposes to the development of interstitial fibrosis. Adaptive and maladaptive repair can be focally variable; tubular damage can resolve completely in some areas, whereas other areas can be less resilient to insults, leading to tubular atrophy. Maladaptive repair and interstitial fibrosis reduce the kidneys’ reserve available to buffer further kidney insults. A negative spiral can then ensue, in which fibrotic damage further increases the risk of subsequent progression and more extensive chronic damage. The finely balanced response to the initial kidney insult, together with the nature and duration of this insult itself, are critical in determining the long-term outcome following AKI [7, 16, 22].

Animal models of AKI have led to the identification of a number of mechanistic pathways that contribute to progression following an acute kidney insult. These include oxidative stress, the DNA damage response pathway, epigenetic changes, mitochondrial dysfunction and the complement pathway, as illustrated in Fig. 2.

Oxidative stress plays a key role in both the development of kidney injury following an acute insult and maladaptive repair and progression following the injury itself [23, 24]. Notwithstanding the contribution of oxidative stress to injury and progression, there is some evidence that this pathway might be beneficial in ameliorating the effects of acute insults in specific circumstances. Ischemic pre-conditioning prior to a kidney insult has been found to reduce the development of AKI [25]. The likely mediators of this protective effect are cellular defense mechanisms, such as hypoxia-inducible factor (HIF) and nuclear factor erythroid 2-related factor 2 (Nrf2), which are activated by the pre-conditioning event [26]. Although potentially beneficial in ameliorating acute injury, pre-conditioning responses can be chronically deleterious [27]. Injury can lead to a reduction in capillary density that can exacerbate renal hypoxia and thereby contribute to progression [28, 29]. The durable effects of ischemic pre-conditioning in AKI require further careful evaluation.

The DNA damage response is a network of signaling pathways that can trigger cell cycle arrest, or cell death, in response to injury. DNA damage response pathways are activated by AKI [30]. Aberrant cell cycle arrest in proximal tubular cells has been implicated in maladaptive repair and the development of fibrosis [31]. Kidney injury can also influence the phenotypic transition of various cells that can lead to progressive damage. Transition of endothelial cells to a mesenchymal phenotype can impair proliferation and exacerbate oxidative stress [32]. Durable structural changes and progression can result from the transition of pericytes to myofibroblasts and from epithelial–mesenchymal transition in renal obstruction [33, 34].

Emerging evidence suggests a role for complement pathways in progression following an acute kidney insult. Knock-out of cell surface complement regulatory proteins from proximal tubular epithelial cells increases susceptibility to progressive injury in ischemia–reperfusion models of AKI [35, 36]. Complement pathway inhibition ameliorates kidney injury in this model. Further work is needed to clarify the exact nature of complement interactions in AKI progression.

It is anticipated that growing knowledge of the mechanisms that underlie progression following AKI will ultimately lead to therapies that may ameliorate long-term sequelae, as discussed further in the section “Future therapies which may ameliorate progression following AKI”.

The identification of children who are most at risk of progression following AKI is necessary in order to target interventions to minimize progression. Risk factors for long-term sequelae following AKI and techniques to stratify the risk of progression in children are outlined in this section.

The severity of a kidney insult is a well-established risk factor for progression following AKI. Insults that are severe and/or prolonged can disrupt the balance of inflammatory and anti-inflammatory factors required to facilitate adaptive repair processes, and thus compromise renal recovery [37, 38]. Multiple acute kidney insults exert a cumulative impact that can hamper adaptive repair and lead to sequelae. Laboratory and clinical observations support this concept. In animal models, the frequency of proximal tubule injury affects renal prognosis [38]. In adult patients with diabetes mellitus, repeated episodes of AKI are associated with end-stage renal disease [39]. Multiple episodes of myohemoglobinuric AKI are closely associated with long-term kidney fibrosis and CKD [27]. The cumulative impact of multiple kidney insults can compromise adaptive repair processes with resultant progression.

Pre-existing CKD confers an increased risk of progression following AKI. Animal studies have demonstrated a propensity for maladaptive repair in the context of reduced renal mass [40]. Clinical studies in both adults and children evidence reduced capacity for functional renal recovery following AKI in patients with pre-existing CKD [7, 22, 41, 42]. This phenomenon represents a high-risk to children with CKD given their lifetime exposure to acute kidney insults.

Many of the risk factors for progression outlined above are challenging to quantify. Strategies with greater discriminative power to identify children at risk of progression are needed. Large data techniques in which electronic health information, such as laboratory values, vital signs and patient characteristics, are used to build prediction models for events have been successfully used to stratify adult patients at risk of developing AKI [43]. Further work is needed to evaluate the application of these techniques to determine progression risk following AKI in both adults and children.

The use of urinary biomarkers to inform the risk of progression following AKI has shown some potential. In adult patients, three biomarkers have been found to predict progression of AKI among patients with acute cardiorenal syndrome, namely urinary angiotensinogen, urinary neutrophil gelatinase-associated lipocalin and urinary interleukin-18 [44]. Whilst studies in neonates and children with AKI have identified biomarkers with some discriminative value for the early identification of AKI [45‐49], their use in risk stratification for progression has not been evaluated to date.

Imaging applications have shown promise in identifying features that may predict progression following AKI. Two magnetic resonance imaging (MRI) techniques, namely diffusion-weighted-MRI and blood oxygen level-dependent-MRI, have been used to evaluate tubulointerstitial alterations and parenchymal hypoxia in patients with both AKI and CKD with some success [50]. Ultrasound and MRI elastography can provide hemodynamic and structural information which may be predictive of progression [51, 52]. Further evaluation of these non-invasive techniques may enhance assessment of progression risk in the future.

There is a clinical need to develop reliable strategies to stratify the risk of progression following AKI in the pediatric population in order to tailor appropriate therapy and follow up with the aim of minimizing long-term sequelae.

Strategies to minimize progression following AKI in children have not been systematically studied to date. Interventions should target removal of kidney insults and optimization of conditions that facilitate adaptive repair. Clinical priorities include optimization of kidney perfusion, removal of iatrogenic insults, attention to urinary drainage and correction of acid–base and electrolyte disturbances.

Whilst current clinical strategies to minimize progression focus on optimization of the microenvironment in order to facilitate adaptive repair, treatments to accelerate recovery are on the horizon. Potential targets for future therapies and their associated biochemical pathways are discussed in this section and summarized in Table 1.

A key pathway with future therapeutic potential is that of hypoxia and oxidative stress, both factors which can mediate progression [23, 24]. A number of relevant therapeutic targets have been identified. HIFs are transcription factors that play a key role in mediating cellular responses to hypoxia. In animal models of AKI, pre-ischemic targeting of the HIF pathway is effective in ameliorating injury and progression in specific circumstances [26, 60]. Similarly, activation of Nrf2, a regulator of cellular resistance to oxidants, has shown promise in attenuating progression [61, 62]. Thirdly, exogenous VEGF, a stimulant of angiogenesis, can exert a protective effect on renal capillaries and ameliorate long-term damage following an acute insult [63]. The above targets have shown promise as potential future treatments that may minimize progression following hypoxic ischemic insults to the kidneys.

Mitochondrial dysfunction, which can result from AKI, presents an additional pathway relevant to progression. Suppression of mitochondrial biogenesis has been demonstrated in animal models of AKI [64] and is likely to promote progression to fibrosis through persistent cellular injury [65]. Therapeutic agents that support mitochondrial biogenesis and function may therefore be beneficial in ameliorating progression in the future.

Epigenetic changes can influence repair and progression following an acute kidney insult. Epigenetic alterations are activated after AKI and include histone modifications, DNA methylation and chromosomal conformational changes [16]. Novel therapeutic agents that target epigenetic alterations have shown promise in animal models of AKI; for example histone deacetylase inhibitors have been found to accelerate renal recovery and reduce fibrosis after AKI in zebrafish and mice [66].

The response of renal tubular epithelial cells to DNA damage is implicated in fibrosis of the kidney. Modifying the cell cycle of renal tubular epithelial cells via inhibition of tumor suppressor p53 and inhibiting downstream signaling from tubular cells in cell cycle arrest can prevent progression and fibrosis [67]. Further translational work is needed to determine if these strategies can ameliorate kidney fibrosis following AKI in the clinical setting.

Whilst the avenues discussed above hold promise for future accelerated adaptive repair in children at risk of AKI progression, they are all several steps away from being evaluated in the clinical setting. For now, the mainstays of clinical management to minimize progression remain optimization of renal perfusion, urinary drainage and the extracellular environment, and minimization of ongoing kidney insults.

Acute kidney injury is common in children treated in hospital, and a significant proportion experience long-term sequelae. Following AKI, adaptive repair processes can result in the recovery of kidney function; conversely, maladaptive repair can lead to progression, defined as a durable change in kidney structure or function detected by biomarkers, imaging studies or histopathology.

Established risk factors for progression include severity of the kidney insult, the cumulative impact of multiple AKI episodes and pre-existing CKD. Further risk stratification using electronic health record data, biomarker panels and imaging modalities are being evaluated.

Clinical strategies aimed at minimizing progression include optimization of kidney perfusion, urinary drainage and electrolyte and acid–base balance, as well as prompt removal of ongoing kidney insults. Future therapies that may accelerate adaptive repair following AKI and ameliorate progression are on the horizon.