Copyright: tashatuvango / 123RF Stock Photo

The birth of automated urinalysis technology and centralized laboratory testing has unfortunately made examination of the urine sediment by physicians a rare event. The search for the kidney “troponin” continues as we try to figure out the best biomarker for AKI.  Despite this, urine sediment examination remains a time-honored test that provides a wealth of information about the patient’s kidney condition and performs favorably as a urinary biomarker. Dr. Mark Perazella discusses this in a recent review in AJKD.

To contrast that, Drs. Kellum and Chawla discuss the cutting edge research in renal biomarkers and the link between AKI and cell cycle arrest in a review article published in NDT in July 2015.

Credit: Kellum and Chawla, NDT, 2016, which is licensed under CC BY-NC 4.0.

The realization that urine output and creatinine give delayed and incomplete information has lead to a search for improved diagnostics for AKI. Appreciation of the mortality and morbidity of AKI makes this a worthy endeavor. It has been speculated that early identification of kidney injury will lead to improved outcomes. A good comparative is using heart failure to define myocardial infarction. Like low urine output and elevated creatinine, heart failure and reduced ejection fraction are

functional cardiac measures; however, if we wait until this point to treat an MI we have lost any chance to intervene.

The Sapphire trial was a derivation and validation study to identify biomarkers for this purpose in critically ill patients at the highest risk of AKI. The discovery phase involved 522 patients and identified two markers (IGFBP7 and TIMP2) that were elevated in patients with moderate to severe AKI before functional measures were abnormal. The markers were then validated in another data set of 728 critically ill patients. The results demonstrated these markers as effective predictors, with an AUC of 0.80 when used together.  NGAL, KIM1, and other known AKI markers were included in the evaluation, but the maximum AUC was 0.72 for these was well below IGFBP7 and TIMP2 when used individually or together. The markers also contributed additional information to a 9-variable clinical model.

Other independent studies, although smaller, have also confirmed value of various AKI markers in ICU and post cardiac surgery patients (see Haase-Fielitz et al; Koyner et al; Coca et al).

A high specificity cutoff of >0.3 (TIMP2 x IGFBP7) has been selected with a good negative predictive value to identify patients at high risk that need closer attention. To date, over 1200 patients have been studied demonstrating confirmatory results in the risk stratification of ICU patients with imminent AKI. This reflects the FDA initiative to provide risk prediction for moderate to severe AKI in the next 12 hours.

A clinical application of these results is also suggested in the paper. Earlier implementation of KDIGO interventions is proposed if the clinician is aware of a high likelihood of progression. A risk assessment scale for post cardiac surgery AKI is also presented that incorporates the TIMP2 IGFBP7 result.

Cell cycle arrest has been previously suggested as important in the pathophysiology of AKI. Both of the markers are associated with G1 cell cycle arrest. This is a protective mechanism to avoid cell division when potentially damaged. Cells that remain in a senescent phase can lead to fibrosis and subsequent CKD.

Long term follow up data on TIMP2 IGFBP7 can be found in another article published by Koyner et al.  This study analyzed results from the Sapphire data. In patients who developed AKI (stage 1), the hazard ratio for biomarker results between 0.3 to 2 was found to be 1.4, and for >2 was 2.16. Composite endpoint used was death or dialysis at 9 months (79% of enrolled patients had 9 month follow up data). The authors conclude that the biomarkers may provide additional information as to which patients with AKI are at risk for death or dialysis.

Nevertheless, is it premature to abandon our good old friend – the urinalysis.  It may be more appropriate to combine urine sediment examination with new candidate biomarkers that enter clinical practice to create a “diagnostic panel” that provides clinicians with a useful battery of diagnostic tests. As Perazella puts it, “we as nephrologists must encourage continued training and maintenance of competency in urine sediment examination.”

Edgar Lerma, MD
AJKD Blog Advisory Board member

Ian Reilly, MD, FACEP

Disclosure: Dr. Reilly has done consulting work for Astute Medical, Alere, Epocal, Zeus Scientific and Intersection Medical. Dr. Lerma is an Advisory Board member for ZS Pharma and has received Research grant.