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Novel biomarkers indicating repair or progression after acute kidney injury

Kashani, Kianousha,b; Kellum, John A.c

Current Opinion in Nephrology and Hypertension: January 2015 - Volume 24 - Issue 1 - p 21–27
doi: 10.1097/MNH.0000000000000090
CIRCULATION AND HEMODYNAMICS: Edited by Matthew R. Weir and Roland C. Blantz
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Purpose of review Although recovery of kidney function following acute kidney injury (AKI) is not uncommon, it is often incomplete and associated with the development of chronic kidney disease (CKD). In order to improve AKI management, there is a critical need to develop a series of tests and biomarkers to detect renal function recovery and identify patients with progressive kidney disease. This article examines the current body of literature in the field.

Recent findings The recently established consensus definition for AKI has resulted in significant advances in pathophysiologic understanding, patient identification, and disease prognostication. Unfortunately, the definition for renal recovery following AKI remains inconsistent. Proteinuria and microalbuminuria – classical markers of CKD progression – have been used and validated for the progression of AKI to CKD. Data on the performance of other biomarkers of kidney repair and the progression toward CKD are very limited. Specifically, the role of novel biomarkers including neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, and nephronectin (NPNT) in the recovery process has been studied, but it has not reached the point of widespread clinical implementation.

Summary There is a critical need for translational and clinical investigations to verify the performance of potential kidney injury repair and progression biomarker candidates in the clinical setting.

aDivision of Nephrology and Hypertension

bDivision of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Clinic, Rochester, Minnesota

cThe Center for Critical Care Nephrology, CRISMA, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA

Correspondence to John A. Kellum, The Center for Critical Care Nephrology, 604 Scaife Hall, University of Pittsburgh, Department of Critical Care Medicine, Pittsburgh, PA 15206, USA. Tel: +1 412 647 8110; e-mail: kellumja@ccm.upmc.edu

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INTRODUCTION

Acute kidney injury (AKI) is a common clinical syndrome among hospitalized patients. Indeed, there is a growing body of literature that demonstrates the rising incidence and severity of AKI over the past few decades. The most likely reasons for the observed increase in AKI incidence include the aging population, increased prevalence of comorbidities such as chronic kidney disease (CKD), chronic heart and liver failure, diabetes, obesity, and hypertension, increases in the use of invasive therapy (e.g. surgery) in older and more chronically ill patients, and the use of more sensitive definitions of AKI [1,2]. Significant morbidity and mortality have been associated with AKI, including progressive CKD and end-stage renal disease (ESRD). For example, in one study, one-fifth of the patients with acute tubular necrosis developed CKD stage 4 [3–8]. Conversely, complete recovery of AKI in comparison with partial or nonrecovery is associated with favorable outcomes [9,10▪]. On the basis of the gravity of AKI and its sequelae, there is a critical need to discover clinical risk models, tests, or biomarkers able to differentiate between patients likely to recover their kidney function or structure, and those likely to develop progressive CKD following an episode of AKI.

During the past decade, the use of consensus definitions of AKI, including RIFLE (Risk, Injury, Failure, Loss, ESRD), AKIN (Acute kidney injury network), and KDIGO (Kidney Disease: Improving Global Outcome), has unified the epidemiological studies [11–13]. Although the AKI definitions have moved the field forward, they do not include explicit criteria for AKI resolution or recovery. The development of tests to predict functional and structural recovery post-AKI and establishment of a consensus definition for structural renal recovery are the next steps on the road to improve the management and prognostication of AKI (Fig. 1). In this article, we will review the current literature regarding diagnostics to predict renal repair and progressive CKD following AKI.

FIGURE 1

FIGURE 1

Box 1

Box 1

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RENAL RECOVERY DEFINITION

Currently, the only consensus definition for recovery of AKI is provided by the Acute Dialysis Quality Initiative (ADQI) group [13]. All current definitions of kidney recovery are based on functional improvement of AKI. Although complete structural reconstitution of kidney may indicate decreased chance of progression to CKD, there is no definition that incorporates structural restoration in the definition of AKI recovery.

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Definition of kidney recovery

Functional recovery of AKI is often defined as liberation from renal replacement therapy (RRT), yet fundamentally this criterion only applies to individuals with the most severe degree of AKI [14]. Less severe stages of AKI are also associated with high morbidity and mortality, and failure to recover from these stages would greatly impact long-term outcomes. Indeed, for many, this would mean worsening of underlying CKD or de-novo CKD, with all the attendant morbidity. Therefore, definitions have emerged which incorporate absolute and relative change in serum creatinine, and outline partial or complete recovery. Some studies have defined renal recovery as an improvement in the serum creatinine concentration to within 10–20% above baseline [14]. This definition is dependent on baseline serum creatinine availability, which is often not easily achievable. In addition, due to the nonlinear relationship between serum creatinine and glomerular filtration rate (GFR), this definition does not provide the real gained GFR given individual patients with different baseline kidney function. Another available definition for functional kidney recovery is a serum creatinine value less than 2 mg/dl. This definition is advantageous in that it ameliorates the need for baseline serum creatinine. Unfortunately, a creatinine value less than 2 mg/dl may be sub-baseline in cases of advanced CKD; therefore its utility in these individuals is limited. Also, although the achievement of a creatinine level below 2 mg/dl may signal a degree of functional recovery, it may still indicate significant deterioration in kidney function among patients with normal baseline kidney function. More importantly, arbitrary cut-offs for creatinine are not clinically meaningful. A 20-year-old black male might have a GFR of 55 ml/min/1.73 m2 with a creatinine of 2 mg/dl, whereas the same creatinine would equate to a GFR of 27 ml/min/1.73 m2 for a 70-year-old white female. To say that both have ‘recovered’ to the same degree would not be logical.

The ADQI group provided the first consensus definition for functional AKI recovery in 2004 [13]. The group suggested complete renal recovery is defined as a return to creatinine less than the threshold for RIFLE-R or within 50% of baseline, whereas partial renal recovery happens if patients are off RRT, but fail to return to within 50% of baseline serum creatinine. Patients who require persistent RRT (RIFLE classification L and F) are classified as nonrecovery. Although this definition gives clinicians and investigators a framework by which to approach renal recovery, it has limitations. This definition not only depends on the presence of baseline serum creatinine but also lacks clarity about the role of urine output in the recovery process. Lastly, the time and setting of AKI onset can affect a clinician's ability to apply this recovery definition.

In addition to the aforementioned limitations of each definition, all of the above criteria for functional renal recovery lack information about the time-course of the recovery process. They do not clarify how long clinicians or investigators need to follow patients to identify recovery of kidney function. On the basis of the current definition, a cut-off of 90 days following AKI is required to reach CKD status. KDIGO has proposed the concept of acute kidney disease (AKD) to address the fate of AKI before 90 days. AKD is defined as a GFR below 60 ml/min/1.73 m2 or evidence of structural kidney damage for less than 3 months [15▪▪]. Although AKD allows better framing of the AKI progress, newer studies indicate that the recovery process could go on for significantly longer periods. In one study, investigators concluded that it takes the kidney at least 12–18 months to recover to a GFR of above 60 ml/min/1.73 m2 among adult survivors of AKI [16].

The above definitions do not address the repair or progression of kidney disease following AKI. The structural and anatomical changes, during recovery of kidney function, are globally ignored in all functional definitions. Following complete renal recovery, as it is defined above, serum creatinine returns close to the baseline level; however, this may not indicate that structural integrity of the kidney has been completely restored, overlooking the fact that it may have important implications on the progression of AKI to CKD that results in long-term functional changes. Animal models showed that nephron loss following AKI could result in glomerular hypertrophy of the surviving nephrons [17]. Other structural changes following AKI could also lead to maladaptive recovery of kidney composition, which, in turn, may trigger the development of progressive CKD. These changes include adaptive repair and regeneration of the kidney functional units, systemic and intrarenal hypertension and hyperfiltration, tubular hypertrophy, tubulointerstitial fibrosis, and glomerulosclerosis [18–20]. The ADQI group provided a pathway to begin building a definition of kidney injury based on both structural and functional biomarkers of AKI (Fig. 2a)[21▪]. One way to think about appropriate definition of renal recovery is to combine the value of functional and repair markers in the definition (Fig. 2b). The top right cell in Fig. 2b – labeled as functional recovery – refers to a condition in which structural changes persist and thus there is ongoing risk, and in which the apparent recovery may be short-lived. Also, there may be a loss of renal functional reserve that we cannot measure [15▪▪].

FIGURE 2

FIGURE 2

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BIOMARKERS OF REPAIR AND PROGRESSION OF ACUTE KIDNEY INJURY

The critical need to improve the care and outcomes of AKI has resulted in significant advancement in the application of novel clinical models and biomarkers for AKI diagnosis, prognosis, and management (Fig. 1). At present, providers have access to one or more injury biomarkers at the bedside for diagnostic or research purposes, but there is limited availability or use of biomarkers specific for repair and progression. Significant effort has been made to predict recovery of AKI or its transition to CKD based on the available clinical variables, including sex, age, race, presence of acute tubular necrosis (ATN) or diabetes mellitus, need for RRT, baseline and hospital serum albumin concentrations, baseline hemoglobin, and mean hemoglobin during hospitalization [4,22▪▪]. Although these clinical models are extremely useful in prognostication of AKI outcomes, there is still a need for confirmatory repair or progression biomarkers. There are a few studies which evaluated the role of current injury biomarkers in the prediction of kidney recovery. In comparison, there is only limited knowledge about repair or progression-specific biomarkers available in the literature. Here, we review the current state of biomarkers in kidney recovery following AKI.

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Use of injury biomarkers to predict kidney recovery or progress to chronic kidney disease

In a recent animal model of ischemic–reperfusion injury (IRI) of the kidney, Havcr1 and Lcn2 [genes that code for kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL), respectively] were found to have the highest activity throughout the investigation period, including both early and late after AKI. Authors concluded that urinary KIM-1 and NGAL may be surrogates for progressive kidney injury following IRI and the AKI-to-CKD transition [23]. In addition, several other animal studies have highlighted that persistent elevations in urinary NGAL and KIM-1 are associated with rapid progression of AKI toward CKD [24–29]. This is further supported by evidence that, among patients who required RRT for AKI, decreasing urinary NGAL and hepatocyte growth factor in the first 14 days was associated with improved odds of being alive and free of dialysis at 60 days from the start of RRT. In addition, they found that patients who recovered from AKI had higher urinary cystatin C on the first day of the enrollment [30]. It has been indicated that cystatin C in the urine can suppress T-cell-mediated immune response by inhibiting cathepsin S activity, and therefore it has the capacity to participate in AKI prevention and potentially renal recovery [31]. Also, in a study of plasma NGAL measured on admission for 189 patients who had community-acquired pneumonia and developed severe AKI, plasma NGAL was found to provide fair information regarding the possibility of kidney function recovery (defined as alive and free of dialysis) with receiving operating characteristic area under the curve (AUC) of 0.74 [32].

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Repair and progress-to-chronic kidney disease specific biomarkers following acute kidney injury

Although the number of studies on reparative mechanisms of the kidney following acute injury has exponentially increased in recent years, currently the body of literature on repair and progression biomarkers of kidney injury is very limited. Application of classic biomarkers of progression from AKI to CKD has shown utility in some subtypes of AKI, but not all patient populations. An example of such a biomarker is proteinuria or microalbuminuria which has been validated in diabetic nephropathy and some subtypes of AKI as a marker of progression to CKD [15▪▪].

Repair and recovery of kidney structure following AKI is a very complex process. This complexity allows investigators to have a large number of candidate proteins which could serve as indicators of repair or progression to CKD. The pathways involved in the recovery and their products involve many different proteins which could be found in the plasma or urine. In a recent study, investigators measured a large number of candidate proteins in the plasma and urine of patients who were at high risk for the development of AKI. This approach resulted in the discovery of two new injury biomarkers of AKI, which were later validated in two large independent cohorts [33,34▪]. Recently, such an approach was used in the discovery of recovery biomarkers. Investigators measured plasma inflammatory and apoptosis markers, along with growth factors, in 817 ICU patients who required RRT for AKI [10▪]. Authors noted that renal recovery was slower in patients who had increased concentrations of plasma interleukin (IL)-8 and IL-18, and tumor necrosis factor receptor-I (TNFR-I). In addition, patients with higher IL-18, macrophage migration inhibitory factor, and TNFR-I experienced higher mortality.

Following damage to the tubular cells, a series of pathways become activated including cytoprotective pathways, also referred to as the ‘renal stress response’. These pathways include heme-oxygenase pathways, heat shock proteins, and stress-activated protein kinases. Recently, the role of AMP-activated protein kinase (AMPK) in the regulation of mammalian target of rapamycin (mTOR) in an animal ischemia–reperfusion model of AKI showed protection of renal tubular cells in this experiment [35]. In addition, tubular cell proliferation and differentiation is associated with release of several proteins from the tubular cells themselves and also from other organs to assist with the recovery process. Apart from growth factors such as epidermal growth factor, hepatocyte growth factor, insulin-like growth factor-I, and fibroblast growth factors, there are immediate early genes and cell cycle signaling pathways to allow cells to enter and complete the cell cycle. Finally, tubular cell migration and differentiation, along with extracellular matrix remodeling following initial damage to the tubular basement membrane, are each essential steps of the repair processes [36]. The above mentioned processes have several mediators that could be measured in AKI patients to test their predictive capability for renal recovery or CKD development.

One example of such a protein is NPNT. NPNT is an a8b1 integrin ligand that is involved in the kidney morphogenesis and is found in the extracellular matrix of the Wolffian duct and the ureteric bud [37,38]. In a murine model of AKI, NPNT was found to be focally present in normal renal tubular epithelium, whereas its expression was significantly increased in regenerating tubular cells during the maintenance and recovery phases of ATN. In addition, NPNT was expressed in regenerating renal tubular cells prior to expression of the proliferating cell nuclear antigen protein [39]. NPNT involvement with the recovery process and its timeline of expression may make it a reasonable target for clinical validation.

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FUTURE DIRECTIONS AND CLINICAL APPLICATION OF KIDNEY INJURY REPAIR AND PROGRESSION BIOMARKERS

Building upon the significant recent progress made in the field of AKI and its biomarkers, the next step is to discover and validate new markers of kidney repair and progression. Such biomarkers could be used to construct a new definition in the AKD spectrum, which balances both functional and structural biomarkers of repair and progression; analogous to the framework recently suggested by the ADQI group (Fig. 2a and b). Such a definition would allow clinicians to provide better prognostication to patients with AKI and develop a more efficient and individualized care plan for them. In addition, it could be used to discover drugs that stimulate and facilitate renal recovery and monitor their effects in future investigations.

Basic, clinical, and translational studies are needed to develop and validate the recovery markers and evaluate their roles in the care of AKI patients. The body of knowledge regarding this very complex recovery process is exponentially growing and provides an excellent ground for future clinical investigations.

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CONCLUSION

Repair and progression biomarkers of AKI potentially play very important roles in the care of AKI patients. Although several pathways and proteins in renal recovery and the AKI-to-CKD transition have been discovered, clinical data regarding the performance of these proteins as biomarkers of renal recovery are limited. Future focus on this topic is a necessity and requires close collaboration between basic scientists, clinical investigators, and bedside clinicians.

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Acknowledgements

We thank Erin N. Frazee, PharmD, for her critical review of the manuscript.

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Financial support and sponsorship

None.

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Conflicts of interest

J.A.K. has received grant support and consulting fees from Alere and Astute Medical.

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REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest
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REFERENCES

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Keywords:

acute kidney injury; biomarker; progression, recovery; repair

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