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• W1999505725 abstract "Urine represents a mine for proteomic markers of renal diseases, but its analysis is hindered by unresolved technical issues. Aregger et al. used an unbiased proteomics approach to analyze urine of critically ill patients. They discovered insulin-like growth factor-binding protein 7 (IGFBP-7) and linked it to acute kidney injury (AKI) outcome. Future efforts should address the biology of IGFBP-7 and related proteins to determine their role in AKI. Urine represents a mine for proteomic markers of renal diseases, but its analysis is hindered by unresolved technical issues. Aregger et al. used an unbiased proteomics approach to analyze urine of critically ill patients. They discovered insulin-like growth factor-binding protein 7 (IGFBP-7) and linked it to acute kidney injury (AKI) outcome. Future efforts should address the biology of IGFBP-7 and related proteins to determine their role in AKI. Even in ancient history, physicians examined urine for clues about patients’ illnesses. The evolution of proteomics has invigorated the quest for improved renal disease biomarkers. Proteins are the main actors in biological processes, and their diversity is much greater than that of genes. Most of the emerging and traditional biomarkers are proteins (examples include troponin, brain natriuretic peptide, and β-HCG). Urine protein excretion rate is a potent marker of kidney disease progression, and it is intuitive to think that the knowledge of specific proteins in urine could refine our understanding of kidney diseases. Urine is the ideal biofluid for the study of kidney diseases. It can be collected noninvasively, and most of the urinary proteome derives from the kidney. Despite its obvious appeal, it has shortcomings that have hindered the translation of discoveries.1.Konvalinka A. Scholey J.W. Diamandis E.P. Searching for new biomarkers of renal diseases through proteomics.Clin Chem. 2012; 58: 353-365Crossref PubMed Scopus (39) Google Scholar There is no unifying method for urine collection and analysis. It remains unresolved whether to add protease inhibitors, whether to deplete high-abundance proteins, and whether to use spot or timed collection. Spot urine collections require adjustment of biomarker concentrations. The most common adjustment factor is urine creatinine. In acute kidney injury (AKI) the steady state is lost, and longer collections may be preferred over spot samples.2.Waikar S.S. Sabbisetti V.S. Bonventre J.V. Normalization of urinary biomarkers to creatinine during changes in glomerular filtration rate.Kidney Int. 2010; 78: 486-494Abstract Full Text Full Text PDF PubMed Scopus (318) Google Scholar The protein composition of urine is influenced by diet, timing of collection, sex, and age. Additionally, urine biomarkers will underperform in patient populations different from the ones used in discovery. For example, when the study population of AKI contains patients with underlying chronic kidney disease, the markers discovered may reflect the underlying disease rather than acute injury itself. Urine proteomic studies are further challenged by a wide dynamic range of protein concentrations, spanning five to ten orders of magnitude.1.Konvalinka A. Scholey J.W. Diamandis E.P. Searching for new biomarkers of renal diseases through proteomics.Clin Chem. 2012; 58: 353-365Crossref PubMed Scopus (39) Google Scholar This makes it impossible to characterize all proteins in a given sample with current technology. The most promising biomarkers are low-abundance proteins that are difficult to measure. Ongoing efforts are attempting to address technical aspects of urine collection and analysis. In discovery-based proteomics, fractionation of complex mixtures is necessary prior to analysis by mass spectrometry (MS), to improve identification of low-abundance proteins. Typical fractionation methods include gel electrophoresis, capillary electrophoresis, and liquid chromatography. Two-dimensional fluorescence-difference gel electrophoresis (2D-DIGE) represents an improvement over prior gel electrophoresis methods. It relies on fluorescent dyes for more accurate relative quantification, requires less sample preparation, and is reproducible. 2D-DIGE, however, suffers from limitations such as incomplete proteome labeling with dyes and poor detection of low-abundance proteins. The in-solution approaches (capillary electrophoresis and liquid chromatography) have higher resolving power and improved coverage of low-abundance proteins. Aregger and colleagues3.Aregger F. Uehlinger D.E. Witowski J. et al.Identification of IGFBP-7 by urinary proteomics as a novel prognostic marker in early acute kidney injury.Kidney Int. 2014; 85 (this issue)Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar (this issue) used 2D-DIGE followed by MS to define novel urine proteins predictive of AKI outcome in intensive care unit (ICU) patients. They collected spot urine samples on day 1 of AKI and compared the urine proteomes of 12 patients with early recovery (ER) (within 7 days from the diagnosis of AKI) and 12 patients with delayed recovery after 7 days, or no renal functional recovery (LNR). Using 2D-DIGE, they identified more than 1000 spots per gel, and 15 spots were differentially regulated (had mean fold expression >2 and P<0.05 between ER and LNR patients). These 15 spots were subjected to MS and identified two isoforms of α1-microglobulin, α1-antitrypsin, apolipoprotein D, cathepsin D, CD59, insulin-like growth factor-binding protein 7 (IGFBP-7), neutrophil gelatinase-associated lipocalin (NGAL), and calreticulin. Six spots could not be identified by MS. The biological variability was high for all selected proteins, as the direction of change was inconsistent across some paired samples. The authors went on to confirm differential regulation of these proteins, using enzyme-linked immunosorbent assay (ELISA) and immunoturbidimetry. Urine protein measurements were adjusted by urine creatinine. Unfortunately, only two (IGFBP-7 and cathepsin D) of six proteins tested were confirmed in the same urine samples used for discovery. The intra-assay variability was reasonable, with coefficients of variation around 10%. The significant strength of the study relates to verification of IGFBP-7 and NGAL in a separate cohort of ICU patients. To this end, the authors identified 14 patients with ER, 14 with LNR, and 12 controls without AKI. Adjusted day 1 urine excretions of both IGFBP-7 and NGAL were significantly higher in LNR than in ER patients, although the range was large. IGFBP-7 was a significant predictor of ER (area under the curve (AUC)=0.74) and severe AKI (AUC=0.77), while NGAL fared better as a predictor of 30-day (AUC=0.78) and in-hospital mortality (AUC=0.81). Urine IGFBP-7 excretion further improved prediction of renal recovery, when combined with clinical parameters (AUC=0.82). The LNR group included 10 patients who had delayed recovery of renal function. The authors reanalyzed this group, and IGFBP-7 remained a significant predictor of recovery. IGFBP-7 is thus proposed as a novel marker of renal recovery in ICU patients on day 1 of AKI. IGFBP-7 is a secreted glycoprotein that binds to insulin growth factors.4.Oh Y. Nagalla S.R. Yamanaka Y. et al.Synthesis and characterization of insulin-like growth factor-binding protein (IGFBP)-7. Recombinant human mac25 protein specifically binds IGF-I and -II.J Biol Chem. 1996; 271: 30322-30325Crossref PubMed Scopus (311) Google Scholar According to the Human Protein Atlas, IGFBP-7 is expressed in glomeruli and tubules of healthy humans. IGFBP-7 plays a role in G1 cell-cycle arrest. Renal tubular cells can enter a short period of G1 cell-cycle arrest following injury from experimental sepsis5.Yang Q.H. Liu D.W. Long Y. et al.Acute renal failure during sepsis: potential role of cell cycle regulation.J Infect. 2009; 58: 459-464Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar or ischemia.6.Witzgall R. Brown D. Schwarz C. et al.Localization of proliferating cell nuclear antigen, vimentin, c-Fos, and clusterin in the postischemic kidney. Evidence for a heterogenous genetic response among nephron segments, and a large pool of mitotically active and dedifferentiated cells.J Clin Invest. 1994; 93: 2175-2188Crossref PubMed Scopus (534) Google Scholar This process may prevent cells from dividing when DNA is damaged and may represent an early response to renal injury. Indeed, IGFBP-7 was recently validated in a large multicenter cohort of ICU patients as a predictor of AKI development (RIFLE criteria for injury/failure).7.Kashani K. Al-Khafaji A. Ardiles T. et al.Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury.Crit Care [online]. 2013; 17: R25Crossref PubMed Scopus (794) Google Scholar IGFBP-7 and tissue inhibitor of metalloproteinases-2 (TIMP-2) outperformed other markers of AKI including urine/plasma NGAL, urine KIM-1, urine interleukin-18, plasma cystatin C, and serum creatinine and had an AUC of 0.8 for predicting AKI onset 12–36h after sample collection. TIMP-2 is another protein involved in cell-cycle arrest, suggesting the importance of this process in AKI. The study by Aregger et al.3.Aregger F. Uehlinger D.E. Witowski J. et al.Identification of IGFBP-7 by urinary proteomics as a novel prognostic marker in early acute kidney injury.Kidney Int. 2014; 85 (this issue)Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar substantiates the potential utility of IGFBP-7, suggesting that it might be a biomarker of AKI prognosis, in addition to predicting AKI onset. There are several caveats to consider. This is not the first study to address prognostic biomarkers of AKI. Multiple other markers have come down the pipeline. NGAL is the most studied biomarker of AKI and predicts the need for renal replacement therapy and mortality.8.Haase M. Bellomo R. Devarajan P. et al.Accuracy of neutrophil gelatinase-associated lipocalin (NGAL) in diagnosis and prognosis in acute kidney injury: a systematic review and meta-analysis.Am J Kidney Dis. 2009; 54: 1012-1024Abstract Full Text Full Text PDF PubMed Scopus (1007) Google Scholar The change in urine NGAL and urine hepatocyte growth factor excretion between day 1 and day 14 of AKI combined with clinical factors demonstrated an AUC of 0.93 for predicting renal recovery at day 60 in ICU patients.9.Srisawat N. Wen X. Lee M. et al.Urinary biomarkers and renal recovery in critically ill patients with renal support.Clin J Am Soc Nephrol. 2011; 6: 1815-1823Crossref PubMed Scopus (119) Google Scholar Urinary interleukin-18 predicted mortality in critical care patients with AKI.10.Parikh C.R. Abraham E. Ancukiewicz M. et al.Urine IL-18 is an early diagnostic marker for acute kidney injury and predicts mortality in the intensive care unit.J Am Soc Nephrol. 2005; 16: 3046-3052Crossref PubMed Scopus (448) Google Scholar These markers were measured at multiple time points, providing information about their dynamic changes. These and other biomarkers require testing in large-scale validation studies to demonstrate their utility in patients with AKI. The timing of urine collection warrants a comment. The authors collected urine on day 1 of AKI. It is often difficult to determine the actual onset of AKI except when the insult is obvious. Additionally, the kinetics of urine IGFBP-7 excretion is unknown. When diagnosis is made by increase in serum creatinine, substantial injury has already taken place. Monitoring IGFBP-7 on day 1 makes practical sense, but it misses the opportunity to address IGFBP-7 as an early marker of AKI. This gap may have been filled by the previous study of IGFBP-7.7.Kashani K. Al-Khafaji A. Ardiles T. et al.Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury.Crit Care [online]. 2013; 17: R25Crossref PubMed Scopus (794) Google Scholar Furthermore, given that steady state is lost during AKI, and that the impact of circadian rhythm on the urine proteome in AKI is unknown, timed collections may be more accurate than spot samples for biomarker monitoring.2.Waikar S.S. Sabbisetti V.S. Bonventre J.V. Normalization of urinary biomarkers to creatinine during changes in glomerular filtration rate.Kidney Int. 2010; 78: 486-494Abstract Full Text Full Text PDF PubMed Scopus (318) Google Scholar The issue of timing of urine collection in relation to kidney injury will have to be addressed, including the dynamic nature of IGFBP-7 excretion. Another weakness of the study relates to the 2D-DIGE method of analysis, which precluded detection of most low-abundance proteins and had a high false-positive rate based on two-thirds of proteins failing ELISA-based confirmation. Finally, the group size was small and brings into question the value of this marker in large and diverse patient populations. Future efforts should focus on establishing the biology of IGFBP-7 in AKI, the necessary bridge from biomarker discovery to validation (Figure 1). As shown in Figure 1, this study stopped with verification of IGFBP-7 and NGAL. Additional verification steps could take advantage of systems biology approaches and data available from independent studies. These approaches help home in on the most promising proteins. For example, an enriched process of IGFBP-7 is negative regulation of cell proliferation and growth, and other related proteins may be of interest. The Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database of protein–protein interactions demonstrates that CXCL10 interacts with IGFBP-7. CXCL10 is a previously discovered marker of AKI.11.Ho J. Lucy M. Krokhin O. et al.Mass spectrometry-based proteomic analysis of urine in acute kidney injury following cardiopulmonary bypass: a nested case-control study.Am J Kidney Dis. 2009; 53: 584-595Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar Mechanistic studies exploring the biology of IGFBP-7 should be pursued. The relevant questions to address include the function of IGFBP-7 in AKI, and the mechanism of its appearance in urine. One might speculate that this protein is secreted by tubular cells rather than filtered, as it is a glycoprotein, present at higher levels in urine of patients with lower glomerular filtration rate. Nonetheless, this question deserves further study. Ultimately, the greatest clinical problem in AKI is defining novel therapeutic targets, and IGFBP-7 and its interactors should be studied in this context. For markers that pass ‘qualification’ criteria, validation studies are needed to evaluate their clinical utility. It remains to be seen whether IGFBP-7 stands the challenges of further inquiry into its role in AKI. The author expresses gratitude to James W. Scholey for his helpful suggestions and mentoring." @default.
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• W1999505725 title "Urine proteomics for acute kidney injury prognosis: another player and the long road ahead" @default.
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