Urine Sediment Exam Provides More Diagnostic Information in AKI than Novel Urinary Biomarkers: COMMENTARY

Performance Characteristics

A 2006 systematic review by Bagshaw and colleagues that utilized urine microscopy to evaluate sepsis-related AKI did not yield promising results (3). However, per Cavanaugh, when urine sediment is examined quantitatively, there is reasonable clinical utility. In a study of 154 patients who were severely ill and received aminoglycosides or other antibiotics, urinary casts measured by microscopy were most abundant in patients with nephrotoxic AKI, and cast concentrations increased as early as 9 days before the sentinel increase of serum creatinine (4). The strength of urine sediment exam in expert hands is perhaps best illustrated by the Perazella scoring index (5). Here, given the appropriate clinical context, clinical pretest probability coupled with urine sediment score has high positive and negative predictive values. Also, the AKI cast-scoring index by Chawla and colleagues revealed that grading of renal tubular epithelial casts and granular casts has excellent interobserver agreement, with an area under the curve of 0.79, predicting nonrecovery of kidney function (6).

A multitude of biomarkers for AKI have been studied, but only the assay for tissue inhibitor of metalloproteinase-2/insulin-like growth factor-binding protein 7 (TIMP-2*IGFBP7) has US Food and Drug Administration approval. Urinary neutrophil gelatinase-associated lipocalin (NGAL) was an early-studied biomarker of AKI in multiple settings. Its mean sensitivity and specificity among several studies ranged between 70% and 80% (7⇓–9). However, comparative data between urine biomarkers and urine sediment were limited. Urine biomarker performance characteristics were generally comparable to, but somewhat less reliable than, urine sediment. In at least one study, urine NGAL was less specific than urine microscopy for AKI as defined by Acute Kidney Injury Network criteria. Importantly, urine sediment examination was conducted only by laboratory technicians in these studies, potentially reducing diagnostic precision (10).

In a large, urinary biomarker validation study of tests for AKI, which did not include urine sediment examination, TIMP-2*IGFBP-7 performed better than other biomarkers, including urine NGAL, IL-18, and kidney injury molecule-1. TIMP-2*IGFBP7 had an area under the curve of 0.80, superior to the other tested biomarkers that had areas under the curve <0.72 (11). These findings are consistent with the TRIBE-AKI study, where all of the aforementioned biomarkers were evaluated except TIMP-2*IGFBP7 (12). On the basis of a series of trials where a cutoff level of >0.3 ng/ml² per 1000 was defined for TIMP-2*IGFBP7, the specificity for detection of AKI was 46%, with a positive and predictive value (precision) of 27%. These studies showed that careful patient selection is critical because low pretest probabilities foster high false positive rates (13,14).

Overall, the limited number of studies of urine sediment examination have revealed its relatively high precision for the diagnosis of AKI. The current literature does not support the contention that urine biomarkers are superior to urine sediment examination for diagnosis of AKI or acute tubular necrosis.

Verdict: Urine biomarkers and sedimentation analysis are tied for performance characteristics.

Reliability and Accuracy

A commonly cited pitfall of urine sediment examination, which Cavanaugh concedes, is a lack of interobserver reliability. Conversely, the Chawla AKI cast-scoring index study demonstrates that sufficient training in urine sediment examination increases interrater reliability. Consequently, we advocate for greater, not lesser, training in this vital cost-effective procedure. Moreover, we advocate for increased utilization of phase contrast microscopy, a common practice in European Nephrology laboratories. In a single-center study that included 121 subjects and used Chawla and Perazella scores, longitudinal urine microscopy analysis showed enhanced diagnostic specificity for AKI compared with single inspection (15). Additionally, serial urine examinations identified 20%–25% of patients with AKI that would have been falsely attributed to a diagnosis of nonacute tubular necrosis kidney injury. Although this result may seem to question the validity of urine sediment scoring, this is not a fair assessment, because study methodology pertaining to inclusion criteria of AKI stage ≥2 and assessment of study end points differ from the original studies of Perazella and Chawla.

By contrast, urine biomarkers such as NGAL and TIMP-2*IGFBP7 have been evaluated in a number of clinical settings and validated in large cohorts, including the SAPPHIRE validation and follow-up studies (11). Specific conditions for which TIMP-2*IGFBP7 is clinically approved include intensive care units with patients who have sepsis or who are undergoing major surgery. However, multiple studies have shown comparable performance of this assay for patients who are in other circumstances, including heart failure, kidney transplantation, and chemotherapy-induced AKI (16). The timing of urine sample acquisition may influence biomarker analysis, particularly in day-to-day practice. For instance, most studies that evaluated urine NGAL used standardized sampling techniques that may not be readily applicable in general practice. Also, the urine TIMP-2*IGFBP7 assay may produce erroneous results with proteinuria, pyuria, or bilirubinuria (17).

Verdict: Urine biomarkers are reliable and accurate; more studies of urine sediment examination are required.

Prognostication and Therapeutic Implications

It is well established that severity of AKI has a graded response to patient prognosis. Nevertheless, our ability to prevent or reverse outcomes from AKI has remained elusive. The ability to recognize a therapeutic window during which time interventions might have a positive effect on AKI outcomes has been the primary catalyst for developing accurate urine biomarker tests. Perhaps, urine biomarkers have shown promise in opening this frontier. When the timing of injury is predictable, as with surgical AKI, TIMP-2*IGFBP7 permits early risk stratification and possible interventions to mitigate the risk of developing surgical AKI. The applicability of TIMP-2*IGFBP7 in other settings such as sepsis is largely unknown. Even so, interventions for AKI are primarily preventive. Consequently, some institutions favor widespread adoption of AKI-prevention strategies (18).

Multiple urine biomarkers facilitate the determination of AKI prognosis. In a multicenter observational study that evaluated biomarkers for predicting persistence of AKI, elevated urinary C-C motif ligand 14 was the most predictive of AKI Stage 3 persisting for ≥72 hours. Aside from C-C motif ligand 14, promoted by La and Koyner, serum proenkephalin-A levels were significantly lower in patients who recovered renal function within 48 hours (odds ratio, 0.31; 95% confidence interval, 0.18 to 0.54) and 1 week (odds ratio, 0.23; 95% confidence interval, 0.12 to 0.45) among the 956 patients in the Albumin Italian Outcome Sepsis trial (19). Similar results were observed in another study of patients with AKI and sepsis (20). More recently, an observational cohort study showed that the dickkopf-3-to-creatinine concentration ratio in urine may independently predict dialysis dependency (21).

The urine sediment approach also bears prognostic significance. A pilot study that used an AKI cast-scoring index revealed renal tubular epithelial cell and granular casts with higher scores correlated with nonrecovery from AKI (6). Urine sediment scores have also been shown to correlate with increasing risk of progressive AKI (22). If one accepts that urine sediments are identifiable after the advent of renal tubular injury, then the aforementioned aminoglycoside study may be a good template for simple investigations of early AKI risk stratification.

Verdict: Urine biomarkers “have the edge” for prognostic ability because of the limited number of urine sediment studies in this subcategory.

Cost Effectiveness

The TIMP-2*IGFBP7 assay was approved by the Food and Drug Administration in 2014; however, it is not utilized robustly. Unfortunately, despite the promise of urine biomarkers for improving management of AKI, no investigation has established that earlier recognition of AKI precludes its progression. Consequently, widespread ordering of urine biomarkers may be considered fiscally unjustifiable at many institutions, whereas urine sediment examination has negligible cost. Although a cost-effectiveness analysis comparing biomarkers and sediment examination has not been carried out, we submit that the latter has favorable incremental cost effectiveness.

Verdict: Urine sediment examination is likely more cost effective than biomarker assays.

Other Considerations

Urine sediment examination for AKI has some inherent advantages. It is multimodal and provides a global overview of the genitourinary system with clues to various disorders in a single test. As knowledge of the significance of urine microscopy has expanded, previously held notions of pathognomonic findings have fallen by the wayside, such as the relative insensitivity of eosinophiluria as a diagnostic for allergic interstitial nephritis (23). Because each urine biomarker is site and disease specific, a single biomarker is unlikely to be diagnostic for all subtypes of kidney injury, given the heterogeneous nature of AKI. Perhaps choosing biomarkers directed to specific disease processes or stages of AKI may provide greater benefit. For example, IL-8, IL-18, and TNF receptor type 1 concentrations have been associated with lower 60-day kidney recoveries among patients who require kidney replacement therapy from AKI (24).

Because of a paucity of data and despite its long history, the examination of urine sediment cannot be deemed unequivocally superior to urine biomarker evaluation of AKI. Moreover, the last decade has witnessed immense growth in the study and development of AKI urine biomarkers. Although the era of new diagnostic frontiers is close at hand, enhancing our ability to identify AKI, more work is required before we can replace the existing tool of urine sediment examination. Widescale use of urine biomarkers will likely lag until targeted therapies for AKI become commonplace. During this interregnum, we must follow the precepts of Addis by fostering expert training in examination of the urine. For now, we may consider biomarker identification as a continuum of urine microscopy that guides and amplifies preventive and therapeutic measures for AKI.

Disclosures

All authors have nothing to disclose.

Funding

None.

Author Contributions

All authors conceptualized the study, wrote the original draft, and reviewed and edited the manuscript.