Perioperative Renoprotection: Clinical Implications

Khaschayar Saadat-Gilani, MD; Alexander Zarbock, MD; Melanie Meersch, MD


Anesth Analg. 2020;131(6):1667-1678. 

In This Article

New Renal Biomarkers

During the last decades, a growing number of new biomarkers have been studied for their suitable use in clinical practice. New markers are Cystatin-C, neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), interleukin-18 (IL18), liver-type fatty acid-binding protein (LFABP), tissue inhibitor of metalloproteinases 2 (TIMP- 2), insulin-like growth factor-binding protein 7 (IGFBP7), and endogenous ouabain. To date, most of them have not found their way into daily clinical practice. The reason for this might be the uncertainty of how to use these damage biomarkers in clinical practice as well as the lacking possibility of measuring them at the bedside by using point-of-care devices. However, some of them will be discussed in further detail.


Cystatin-C is a low-molecular-weight protein (13.3 kDa) with protective function by inactivating endogenous cysteine proteinases which are responsible for proteolysis and tissue damage. Cystatin-C is freely filtered in the glomerulus and reabsorbed in the tubular system but does not undergo tubular secretion (in contrast to creatinine), thereby being a more reliable marker in detecting a GFR decline 1 to 2 days earlier than serum creatinine.[44] Additionally, it shows better predictive properties for death and cardiovascular events in elderly patients compared to creatinine.[45]

Cystatin-C has been shown to be superior to serum creatinine in detecting estimated GFR (via Modification of Diet in Renal Disease equation) reduction, and these findings have been confirmed in a meta-analysis.[46] It seems that Cystatin-C is less affected by body weight, age, or sex compared to serum creatinine. However, corticosteroids, hyperthyroidism, inflammation, or hypertriglyceridemia seem to influence plasma levels significantly.[47,48]

Cystatin-C is a functional marker and therefore not appropriate for early detection of renal damage. In addition, the costs and the limited availability in some regions reduces the use in clinical practice.

Neutrophil Gelatinase-associated Lipocalin

NGAL, a 25-kDa protein, is synthesized during granulocyte maturation in the bone marrow[49] and may be induced in inflammatory processes like inflammatory bowel disease and malignancies.[50] It is also considered a marker of tubular damage.[51] Studies in pediatric and adult cardiac surgery were able to demonstrate a rise in NGAL levels 1 to 3 days earlier compared to serum creatinine increases. The predictive value of NGAL was higher in pediatric patients as compared to adults due to the higher presence of comorbidities.[52] Different comorbidities, like chronic kidney disease, alter the predictive value of NGAL, because these conditions may modulate baseline levels. After surgery, it has been shown that NGAL levels were significantly higher in patients who develop AKI.[53] A recent meta-analysis of 19 studies including over 2500 patients demonstrated the ability of serum and urinary NGAL to predict the need for RRT and overall mortality.[54] Some studies could demonstrate NGAL elevations being an independent predictor of major cardiovascular events and mortality.[55,56] One important finding resulted from a pooled analysis of prospective studies where it was demonstrated that an NGAL elevation in the absence of a serum creatinine increase was associated with an increased risk of adverse outcomes.[36] Based on these data, the term "subclinical AKI" was introduced which describes a state of kidney damage without a loss of function.[57]

However, the major drawback of NGAL is the fact that 2 isoforms exist, and available antibodies are not able to distinguish between these 2 isoforms. This means that it is impossible to differ between AKI and inflammation. It is important to know that serum NGAL levels reflect inflammation, whereas urinary NGAL levels can reflect inflammation (filtered in the glomerulus) or tubular damage.

Tissue Inhibitor of Metalloproteinases 2 and Insulin-like Growth Factor-binding Protein 7

TIMP-2 and IGFBP7 have been isolated among over 300 markers in a heterogeneous group of critically ill patients[58] and have shown the ability to predict the development of moderate or severe AKI within 12 hours of sample collection. Although individually each has performed better in different subgroups of patients (TIMP-2 in surgical and IGFBP7 in sepsis-induced AKI patients), they seem to have additive predictive value and multiplication of both [TIMP-2] × [IGFBP7] resulted in an improved area under the curve (AUC) of 0.80 (compared to 0.76 and 0.79, respectively). Unlike other biomarkers, [TIMP-2] × [IGFBP7] also allowed to differentiate between AKI and non-AKI conditions. Both biomarkers are expressed in early phases of cell injury resulting in G1 cell cycle arrest.[59,60] This prevents the further replication of potentially damaged DNA. Initial smaller studies in 50 cardiac surgery patients were showing conflicting results, describing weak test performance without predictive value.[61,62] However, a single-center trial was able to identify patients at high risk of AKI by measuring urinary [TIMP-2] × [IGFBP7] levels early after cardiac surgery.[63] Later studies added to the growing body of evidence confirming the utility of [TIMP-2] × [IGFBP7] to identify at-risk patients earlier in the clinical setting.[64–66] The prospective properties of this biomarker seems to go beyond AKI. In the critically ill population, [TIMP-2] × [IGFBP7] seems to be able to identify patients at risk for developing other adverse outcomes, namely necessity of RRT or intensive care unit (ICU) mortality, independently from the development of AKI.[67,68] The use of these biomarkers may be a promising opportunity because interventions at the time point of renal damage (before loss of function) might be the window of opportunity for implementing preventive measures to prevent AKI.[58]