Biomarkers in Acute Kidney Injury and Beyond

At present, the renal community suffers from a limited array of noninvasive tools in routine clinical use that can accurately and rapidly identify acute kidney injury (AKI) and generate useful prognostic information to help guide current therapy and anticipate major subsequent events, some of which may require substantial interventions, such as initiating renal replacement therapy.

Similar to cardiology and the use of troponins in acute myocardial infarction, there is an urgent need for new biomarkers to help guide the treatment of patients with renal disease. The study of biomarker applications in renal disease continues to cover a broad spectrum of clinical conditions, including AKI, chronic kidney disease (CKD), and ESRD, including dialysis and transplantation. Within each of these entities, multiple potential applications continue to be evaluated.

In AKI, for example, biomarkers have been studied in terms of early identification of AKI given the well known limitations of changes in serum creatinine in signaling an acute decline in GFR. Biomarkers are also being studied in terms of their predictive capability, for example, to predict the risk of AKI resulting in a need for renal replacement therapy or to predict the risk for development of CKD. In the latter scenario, this may result either from a failure of renal function to return to baseline or perhaps is a result of renal damage, which may not be detectable on the basis of serum creatinine and urine protein measurements but is nevertheless sufficient to result in a course leading to CKD and ESRD.

New biomarkers may have great potential application in CKD as well. For patients with established CKD, among many critically important clinical questions are the risk of progression to ESRD and the risk for cardiovascular morbidity and mortality; hence, biomarkers continue to be investigated for potential utility to address these issues. For patients with ESRD who are on dialysis, the ability to manage the disproportionate cardiovascular morbidity and mortality from which these patient suffer might be aided substantially if biomarkers that could help guide therapy and prognosis were available. For patients with ESRD who undergo renal transplantation, there are numerous clinical issues for which biomarkers that are being actively studied could have an enormous effect, including early detection of allograft dysfunction and differentiation of acute rejection from other causes of allograft dysfunction, including BK virus nephritis, with the goal of reducing the need for allograft biopsy (1). Another major area of investigation has been using biomarkers to help generate an immunologic profile of the transplant patient and guide immunosuppressive therapy to help prevent over- or undertreatment to prevent rejection (2). Here, we will briefly highlight a few examples of clinical scenarios and the potential value of having improved biomarkers.

AKI—radiocontrast nephropathy

Ischemic AKI has served as an important model in which to study new biomarkers, and progressive insights continue to be obtained into the roles of biomarkers as early and accurate indicators of ischemic AKI. There is ongoing investigation into many other aspects of biomarkers, including their mechanistic contribution to AKI as well as their ability to provide prognostic information to facilitate anticipation of the need for renal replacement therapy and more individualized therapeutic interventions. For example, findings from the Translational Research Investigating Biomarkers and End Points for AKI Consortium in patients undergoing cardiac surgery have provided strong support not only for the potential for biomarkers to identify AKI at earlier time points but also to identify patients at risk for other adverse outcomes (3). The scope of AKI biomarker research has continued to extend well beyond ischemic AKI.

/kidneynews/9_8/10/graphic/10f1.jpg

The past year has seen ongoing work on biomarkers in the setting of AKI from various nephrotoxins, including radiocontrast, liver disease, multiple myeloma, hypertensive renal injury, and urinary tract obstruction, among others. Despite the introduction of low- and iso-osmolar radiocontrast, the incidence of contrast-induced AKI remains a common clinical problem likely due to several factors, including an increase in radiographic procedures being performed and an aging population with increased frequency of comorbidities, such as diabetes, CKD, and atherosclerotic disease (4).

The pathophysiology of contrast-induced AKI is thought to be the result of renal ischemia compounded by renal vasoconstriction (5). Contrast-induced AKI has been associated with prolonged hospitalization and represents an independent predictor of unfavorable outcome (6). Currently, contrast-induced AKI is still diagnosed using changes in serum creatinine with its inherent limitations, including its variable production rates among diverse individuals; its secretion in the proximal tubule, which can be altered by drugs; and the time required for a rise in serum creatinine to become evident and thereby indicate the development of an acute reduction in GFR and renal damage. The time required for an elevation of serum creatinine and the resultant delay in the diagnosis of AKI not only limit any opportunity to potentially avert the development of renal damage but also may contribute to prolonging hospital stays in patients undergoing serial serum creatinine measurements who did not develop AKI and in whom a biomarker could have answered this question shortly after the procedure was done.

The term subclinical AKI refers to a change in biomarker level alone without evident simultaneous loss of kidney function. This condition has been associated with increased risk of adverse outcomes in long-term follow-up. One promising biomarker to detect contrast-induced AKI earlier is neutrophil gelatinase-associated lipocalin (NGAL). NGAL and, more specifically, urinary NGAL were shown to be useful in early diagnosis of contrast-induced AKI and in prognosis of AKI (i.e., prediction of initiation of renal replacement therapy and hospital mortality) (7). They can be readily measured by ELISA, but presently, further studies are warranted, because the optimal test (blood or urine), timing, and cutoff value still need to be clarified.

AKI in oncology

AKI in the setting of cancer and cancer therapy is a well known and common clinical problem. Examples of groups at high risk for AKI are patients with acute lymphoma or leukemia undergoing induction chemotherapy. One study reported at least one third of such patients developing AKI, with those requiring renal replacement therapy experiencing a mortality of more than 60% (8). Although years ago cisplatin-induced acute tubular necrosis was a predominant AKI scenario, multiple new agents introduced over recent years, including antiangiogenesis drugs, tyrosine kinase inhibitors, and mAbs, have vastly expanded the spectrum of mechanisms of renal injury.

The growth of these oncologic therapies with a growing list of mechanisms of renal injury has presented a great challenge to nephrology and an urgent need for improved means of prevention, identification, and therapy for AKI in cancer patients. It is worth emphasizing that the consequences of cancer therapy–induced AKI can extend far beyond the acute injury itself, regardless of whether a need for renal replacement therapy results. Some patients will experience only a partial recovery or no recovery at all and are left with permanent parenchymal damage. For those not requiring permanent renal replacement therapy, they can still be left with a reduced GFR and multiple attendant complications, including an increased risk of development of ESRD.

An additional vexing problem facing patients and their oncologists and nephrologists may be the need to delay or abandon certain chemotherapeutic agents when renal damage occurs, with the potential to thereby worsen oncologic outcomes. One area in which biomarker research has been carried out is AKI in the setting of cisplatin chemotherapy. Cisplatin is part of many chemotherapy regimens, and significant nephrotoxicity is most commonly the result of tubular toxicity. Several biomarkers, such as kidney injury molecule-1 (KIM-1), urinary NGAL, and L-type fatty acid binding protein (L-FABP) have been investigated. Urinary NGAL has been shown to be significantly elevated before the rise in serum creatinine, and also, it predicted residual kidney dysfunction weeks later (9). These are promising developments, but further research is needed.

Biomarkers in drug development and nephrotoxicity

It should also be noted that, in addition to the potential for clinical utility of new biomarkers for monitoring for adverse effects of drug therapy, such as oncologic therapies, biomarker research should have a great effect on the field of drug development. Monitoring for renal toxicity is critical to the process of drug development. Biomarkers that can identify nephrotoxicity early in the course of AKI can potentially help protect study participants from developing major acute renal complications as well as permanent renal damage, while potentially allowing for greater testing of drugs where such concerns exist. It should also be noted that this is an area where collaboration between academic institutions and pharmaceutical research companies may be especially productive.

Chronic kidney disease

Research on the use of biomarkers in CKD and the risk of developing CKD also continues, with various applications being explored. The risk of development of CKD in patients who suffer an episode of AKI is an important clinical question, but serum creatinine levels after an AKI event may not be able to identify all patients at risk for CKD.

In one study of children undergoing surgery for congenital heart disease with cardiopulmonary bypass, when those with AKI were compared with those without AKI 7 years later, those who had suffered AKI had higher levels of IL-18 and L-FABP, despite having comparable renal function and urine protein excretion (10). There is also great interest in the potential application of biomarkers in predicting outcomes in CKD, such as cardiovascular events and progression to ESRD. The list of agents being studied in this domain is growing and includes some that have been well studied in AKI, such as NGAL and KIM-1 (11), and others, including soluble tumor necrosis factor receptors and fibroblast growth factor-23. In addition to AKI and the subsequent risk of development of CKD, another potential area where there may be utility of new biomarkers is the ability to predict later development of CKD in patients who undergo nephrectomy. For example, patients undergoing nephrectomy for renal cell carcinoma who had overexpression of miR-193b-3p were found to have a high risk of developing CKD (12).

Potential future applications of biomarkers

The clinical relevance of the growing body of biomarker research has not been unquestioned. For example, the lack of effective interventions in the clinical setting to ameliorate or reverse the course of AKI has served as an argument against the value of having biomarkers that can detect AKI at earlier time points than can be achieved with serum creatinine measurements and urine output. A counterargument is that, in parallel with biomarker research regarding identification and prognostication of AKI, there is ongoing research investigating mechanisms of renal injury and recovery in AKI and therapeutic maneuvers that could ultimately be developed to treat AKI. Such interventions will almost certainly require an accurate determination of the time of onset of injury and detailed information during the subsequent time course. It is noteworthy that some unsuccessful clinical trials of agents to accelerate recovery of AKI, agents that worked well in animal models, have likely been hampered by lack of accurate knowledge of this time course and the inability to detect early AKI by relying on serum creatinine levels. After such therapies are available, it can be argued that having biomarkers for the early identification and prognostication of AKI should be invaluable.

August 2017 (Vol. 9, Number 8)

References

1. Menon M, et al. A peripheral blood gene expression signature for subclinical acute rejection and associated long-term graft injury. Am J Transplant 2014; 14:220–232.

2. O’Connell PJ, et al. Biopsy transcriptome expression profiling to identify kidney transplants at risk of chronic injury: A multicentre, prospective study. Lancet 2016; 388:983–993.

3. Parikh CR, et al. Postoperative biomarkers predict acute kidney injury and poor outcomes after adult cardiac surgery. J Am Soc Nephrol 2011; 22:1748–1757.

4. Andreucci M, Solomon R, Tasanarong A. Side effects of radiographic contrast media: Pathogenesis, risk factors, and prevention. Biomed Res Int 2014; 2014:741018.

5. Michael A, et al. Molecular mechanisms of renal cellular nephrotoxicity due to radiocontrast media. Biomed Res Int 2014; 2014:249810.

6. McCullough PA. Contrast-induced acute kidney injury. J Am Coll Cardiol 2008; 51:1419–1428.

7. Haase M, et al. The outcome of neutrophil gelatinase-associated lipocalin-positive subclinical acute kidney injury: A multicenter pooled analysis of prospective studies. J Am Coll Cardiol 2011; 57:1752–1761.

8. Lahoti A, et al. Predictors and outcome of acute kidney injury in patients with acute myelogenous leukemia or high-risk myelodysplastic syndrome. Cancer 2010; 116:4063–4068.

9. Gaspari F, et al. Predicting cisplatin-induced acute kidney injury by urinary neutrophil gelatinase-associated lipocalin excretion: A pilot prospective case-control study. Nephron Clin Pract 2010; 115:c154–c160.

10. Cooper DS, et al. Follow-up renal assessment of injury long-term after acute kidney injury (FRAIL-AKI). Clin J Am Soc Nephrol 2016; 11:21–29.

11. Alderson HV, et al. The associations of blood kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin with progression from CKD to ESRD. Clin J Am Soc Nephrol 2016; 11:2141–2149.

12. Trevisani F, et al. MicroRNA 193b-3p as a predictive biomarker of chronic kidney disease in patients undergoing radical nephrectomy for renal cell carcinoma. Br J Cancer 2016; 115:1343–1350.