Perioperative Acute Kidney Injury

Sam D. Gumbert, M.D.; Felix Kork, M.D., M.Sc.; Maisie L. Jackson, M.D.; Naveen Vanga, M.D.; Semhar J. Ghebremichael, M.D.; Christy Y. Wang, M.D.; Holger K. Eltzschig, M.D., Ph.D.


Anesthesiology. 2019;132(1):180-204. 

In This Article

Diagnosis of Perioperative Acute Kidney Injury

Diagnostic Criteria Utilizing Creatinine and Urine Output

Multiple definitions and measurements to diagnose acute kidney injury have been explored and studied over the past 30 years. Measurements of serum creatinine and urine output remain the foundation of acute kidney injury diagnosis because they are both easily measurable and distinct to the kidney. The Risk, Injury, Failure, Loss, End-stage renal disease and Acute Kidney Injury Network criteria were each developed with the goal of creating a standardized definition of acute kidney injury that would also allow early and accurate diagnosis and treatment.[12,74] In 2012, the Kidney Disease Improving Global Outcomes classification system emerged and remains the primary classification system for acute kidney injury.[14]

Diagnostic Difficulties in the Perioperative Period

Despite the development of a uniform standard to define acute kidney injury, the Kidney Disease Improving Global Outcomes classification system still has recognized limitations, particularly in the perioperative period. Urine output is a sensitive detection tool for identifying acute kidney injury and is appropriately included in all acute kidney injury definitions. However, the perioperative period has shown to be a unique environment with its own diagnostic challenges. Studies have shown that urine output frequently is decreased in the intraoperative and postoperative period because of the release of aldosterone and vasopressin from stress, hypovolemia, or even anesthesia.[75,76] A 2010 study noted that during surgery, only 5 to 15% of a crystalloid volume load is excreted in the urine, as opposed to 40 to 75% in a nonanesthetized patient.[75] This decrease in urine output was unchanged whether the anesthesia was performed using isoflurane or a propofol infusion. Several studies have examined the relationship between fluid administration and intraoperative urine output and its correlation with postoperative acute kidney injury. One such randomized prospective study examined 102 patients undergoing bariatric surgery who received either high- or low-volume amounts of lactated Ringer's solution.[76] The authors failed to find a correlation between low urine output in the intraoperative period and postoperative acute kidney injury.[76] In conclusion, urine output is a less useful criterion for diagnosing perioperative acute kidney injury, necessitating a need for other diagnostic methodologies.

Serum creatinine is also a flawed diagnostic tool and can be an inaccurate marker for glomerular filtration rate. As a primary diagnostic criterion for acute kidney injury, serum creatinine is problematic because of the temporal delay from injury to the necessary diagnostic rise in creatinine. Creatinine will begin to rise after the glomerular filtration rate is decreased by 50%.[77] An initial creatinine rise may occur on postoperative day 1; however, the clear majority of patients fail to meet criteria for acute kidney injury until postoperative day 2. Because of this "creatinine blind window of acute kidney injury," perioperative acute kidney injury is frequently recognized late in the kidney injury process. Serum creatinine can also be altered by a variety of other factors than kidney junction, many of which are common in the perioperative period, including muscle injury, volume overload, nutrition, and steroids.[77] In summary, the clinical practice of predominantly basing the clinical diagnosis of acute kidney injury on measurements of serum creatinine has many limitations, such as a delay in diagnosing early stages of acute kidney injury. Research into the efficacy of novel biologic markers is ongoing to improve the identification and treatment of acute kidney injury.

Novel Acute Kidney Injury Biomarkers

The utility of biomarkers as reliable measurement tools for detecting minor but significant renal injury has been a focus of translational and bench research. As shown in Supplementary Digital Content 2 (, there are numerous ongoing clinical trials to further sharpen our view and clinical approaches for novel acute kidney injury biomarkers (Supplementary Digital Content 2, A highly precise biomarker would be ideal for renal injury and sensitive from insult to resolution (e.g., accounting for the "creatinine blind" window). Currently, biomarkers showing the most promise all have differing levels of sensitivity and specificity for acute kidney injury, with vastly differing time courses. They are described in more detail below (Figure 4).[78]

Figure 4.

Biomarkers over time after acute kidney injury (AKI). Schematic representation of the levels of several biomarkers over time. The baseline (time 0) is immediately after cardiac bypass (CBP). The lines are a schematic of the predicted rise and fall of the biomarkers after CBP as a function of time and when levels become significant enough to cross the threshold for diagnosing AKI. These patterns and specifically the timeline for diagnosing AKI represent ideal circumstances (the shortest possible time interval shown in a clinical study) and not necessarily what will prove to be clinically verifiable. Cystatin-C, serum cystatin C; IGFBP7, insulin-like growth factor binding protein 7; KIM-1, kidney injury molecule-1; NGAL, neutrophil gelatinase-associated lipocalin; TIMP-2, tissue inhibitor of metalloproteinase 2. Reprinted with permission.78

The neutrophil gelatinase-associated lipocalin molecule is absent in the urine and plasma of healthy individuals. The molecule was initially discovered in a screening study that was designed to identify genes that are differentially expressed in the early periods after renal ischemia. By clamping the renal artery in mice for 45 min, cDNA microarrays were used to define changes in renal gene expression. The authors identified seven upregulated genes, including neutrophil gelatinase-associated lipocalin, an easily measurable stable polypeptide found in the urine during the kidney injury process.[79,80] However, point-of-care testing is unable to detect the renal isoform of neutrophil gelatinase-associated lipocalin. Initial studies showed promise as a predictive indicator of acute kidney injury within cardiac surgery cases, where urine neutrophil gelatinase-associated lipocalin levels are diagnostic of acute kidney injury at 2 h postcardiac bypass.[78,80] In a pediatric trial, similar findings in CPB patients were observed with neutrophil gelatinase-associated lipocalin levels elevated in acute kidney injury patients within 2 h, compared with 1 to 3 days for diagnostic creatinine levels.[81] Criticism of these early neutrophil gelatinase-associated lipocalin trials was the homogenous study population and comorbidity exclusion criteria.[81–83] Subsequent studies with heterogeneous surgical populations found no association between neutrophil gelatinase-associated lipocalin and acute kidney injury.[84,85] An examination of noncardiac surgery cases, showed higher levels of urine and serum neutrophil gelatinase-associated lipocalin among those who have diabetes mellitus, an infection, and chronic kidney disease but failed to correlate an association between neutrophil gelatinase-associated lipocalin levels and acute kidney injury.[84] Specificity of neutrophil gelatinase-associated lipocalin has been estimated to range between 70 to 80%; however, sensitivity is unpredictable, varying from 40 to 90%.[78] The reason for such discrepancy is uncertain. However, neutrophil gelatinase-associated lipocalin levels may be affected by a wide range of factors, such as infections, certain tumors, cardiovascular disease, preexisting renal disease, age, and diabetes mellitus. The influence of confounding variables has raised concerns regarding its diagnostic performance.[86,87] Research is still ongoing for neutrophil gelatinase-associated lipocalin with several studies evaluating opportunities in contrast-induced nephropathy and utilizing neutrophil gelatinase-associated lipocalin to project whether there will be a need for renal replacement therapy.[88,89] Better defining which patient populations will benefit from neutrophil gelatinase-associated lipocalin as a diagnostic tool and its role in combination with other biomarkers is the next step in the research of this important protein.

Another promising biomarker is kidney injury molecule-1. Kidney injury molecule-1 is a type-1 membrane glycoprotein that is upregulated after an ischemic or nephrotoxic injury to the proximal tubule epithelial cells.[90] Studies show that kidney injury molecule-1 functions as a cell adhesion molecule in the reconstruction of injured proximal tubules.[78] A trial examining the occurrence of acute kidney injury during cardiac surgery in pediatric cases found kidney injury molecule-1 to be an excellent diagnostic molecule with elevated urine levels within 6 h after cardiac bypass.[91] However, another study in adult cardiac surgery patients showed good specificity but a sensitivity of only 50% when using urinary kidney injury molecule-1 to diagnose acute kidney injury.[92] This study, along with others, showed that kidney injury molecule-1 is potentially more useful when used as part of a panel combining several biomarkers.[91,92] However, there is currently no point-of-care device in the marketplace for immediate assessment of kidney injury molecule-1.

Cystatin C is unique in that it is a very small, charged molecule completely filtered at the glomerulus where it undergoes catabolism by proximal tubule cells. Because of this, there is virtually no measurable cystatin C found in the urine of healthy kidneys.[78] The above characteristics and a short half-life in the serum (2 h) have made several investigators propose that serum cystatin C is an ideal surrogate for glomerular filtration rate and tubular cell integrity.[78,93–95] Two studies examining the use of serum cystatin C have had mixed results, with one showing its ability to diagnose acute kidney injury occurring within 6 h after surgery, whereas the other found it to be no better than creatinine.[92,93] However, this study did show that urine cystatin C levels rose within 6 h after bypass in those with acute kidney injury, necessitating further study to clarify its role.[96] Currently, the number of patients studied utilizing cystatin C is small, making the results and future of this molecule as a novel acute kidney injury biomarker still to be seen.

Tissue inhibitor of metalloproteinases-2 and insulin-like growth factor binding protein-7 get released during cell cycle arrest and could potentially present sensitive and precise biomarker molecules for diagnosing acute kidney injury.[97] During normal cell proliferation, a cell must go through each stage of the cell cycle (G1–M).[98] However, when cells are damaged, they utilize cell cycle arrest as a protective mechanism to circumvent replication of damaged DNA.[98] When renal cells enter cell cycle arrest, this adaptive response is mediated by surrounding cells through the release of tissue inhibitor of metalloproteinases-2 and insulin-like growth factor binding protein-7.[98] Their presence in the urine is hypothesized to be one of the earliest signs of cellular kidney damage.[97,98] Tissue inhibitor of metalloproteinases-2 and insulin-like growth factor binding protein-7 biomarkers were identified and consequently confirmed in the second phase of the Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) trial, which examined samples from over 700 patients across 35 centers.[97,98] Univariate analysis showed that tissue inhibitor of metalloproteinases-2 and insulin-like growth factor binding protein-7 levels of more than 2.0 ([ng/ml] 2/1000) correlated to an elevated risk of all-cause mortality or renal replacement therapy (hazard ratio, 2.11; 95% CI, 1.37 to 3.23; P < 0.001). In a multivariate analysis adjusted for the clinical model, tissue inhibitor of metalloproteinases-2 and insulin-like growth factor binding protein-7 levels of more than 0.3 ([ng/ml] 2/1000) were associated with death or renal replacement therapy among subjects who developed acute kidney injury.[97] The SAPPHIRE trial also determined that the combination of the two biomarkers proved to be of greater prognostic value for acute kidney injury than either in isolation. Tissue inhibitor of metalloproteinases-2 and insulin-like growth factor binding protein-7 was appreciably more predictive to previously described markers of acute kidney injury (P < 0.002), such as neutrophil gelatinase-associated lipocalin and kidney injury molecule-1, in a heterogeneous population.[98] A recent meta-analysis found they accurately predicted the probability to develop acute kidney injury and subsequent necessity for renal replacement therapy with a sensitivity and specificity of 0.69 and 0.81, respectively.[99] These numbers are promising and will be the focus of several upcoming translational studies to determine its clinical application.

Although several studies were able to demonstrate a statistical association between biomarker level and acute kidney injury, it has been more difficult to prove that biomarker measurements alter clinical outcomes. A recent study comparing the use of a furosemide stress test (which involves giving an IV dose of furosemide followed by 2 h of close urine output monitoring) was equally or more effective at predicting acute kidney injury and necessity of renal replacement therapy than several biomarkers, including neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, and tissue inhibitor of metalloproteinases-2 and insulin-like growth factor binding protein-7.[100] This shows that we should not necessarily forget about previously used methods of acute kidney injury diagnosis, such as urine output and creatinine, but can potentially find other modalities to complement and enhance their diagnostic capability. This is especially true in the perioperative period, during which urine output cannot be relied on as an accurate indicator of acute kidney injury.

The future of biomarkers remains an active and dynamic area of intense research, with translational studies merging biomarker "panels" with existing diagnostic criteria to improve detection and intervention. A promising recent study examined several renal biomarkers, including kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, and cystatin C, and failed to show that any of them alone were better at predicting the necessity of renal replacement therapy or hospital mortality than changes in creatinine.[101] However, when the biomarkers were combined, along with a measure of change in creatinine, they could predict adverse events with excellent sensitivity and specificity. NephroCheck (Astute Medical, USA) was authorized by the U.S. Food and Drug Administration in 2014 as a point-of-care urinary biomarker assay to evaluate acute kidney injury development.[102] This in vitro urine assessment quantitatively measures tissue inhibitor of metalloproteinases-2 and insulin-like growth factor binding protein-7 with reference intervals established in healthy adults and stable chronic morbid conditions without preexisting acute kidney injury.[102,103] Daubin et al.[104] evaluated the NephroCheck in critically ill patients and determined acute kidney injury patients have a significantly higher score than patients without acute kidney injury (0.43 [0.07 to 2.06] vs. 0.15 [0.07 to 0.35]; P = 0.027). However, the authors noted that NephroCheck was unable to distinguish between temporary and persistent acute kidney injury.[104]

The future of point-of-care testing is bright, but significant confounding hurdles must be accounted for to validate the integration of point-of-care testing with biomarker panels. As more biomarkers become commercially available, translational research is necessary to evaluate the efficacy of biomarker panels and point-of-care testing to allow for early intervention, risk assessment, and diagnosis of acute kidney injury.