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Identifying Urinary Renal Scar-Associated Marker Proteins (SCAMPs) Secondary to Pyelonephritis
John Froehlich, PhD1, Rosalyn M. Adam, PhD1, Xin Wang, PhD2, Juan de Dios Ruiz-Rosado, PhD2, Yang Tang, PhD1, Barnali Das, PhD1, Brian Becknell, MD, PhD2, Richard Lee, MD1.
1Department of Urology, Boston Children's Hospital, Boston, MA, USA, 2Kidney and Urinary Tract Center, Nationwide Children’s Hospital, Columbus, OH, USA.
BackgroundUp to 50% of children with urinary tract infections (UTIs) develop pyelonephritis, which can cause renal scarring. DMSA is the gold standard to identify renal scarring (RS), but DMSA is not readily available, is invasive, and has inherent radiation. A non-invasive biomarker that identifies pyelonephritic renal scarring (PN-RS) would be of significant clinical value and potentially lead to novel therapies to reduce injury. We performed proteomics on urine from children with vesicoureteral reflux (VUR), pyelonephritis (PN) and DMSA studies to identify Scar-Associated Marker Proteins (SCAMPS).
Methods A cohort of 100 children was formed, and samples were obtained via an IRB-approved protocol. The cohort included controls (n=32), VUR post-PN with
positive DMSA (n=40), VUR post-PN with
negative DMSA (n=13), and kidney urine from children with ureteropelvic junction obstruction (UPJO) and low kidney function < 40% (n=15). Samples underwent standard handling and proteomic analysis. Comparative analysis was performed between + DMSA, – DMSA patients and controls. Additional analysis involved comparison to UPJO markers and controls to further refine SCAMPS from generalized renal damage markers. Data were compared to a published murine renal transcriptomic PN study to assess pathology and underlying origin of the markers.
Results 3,286 total proteins were identified, of which 820 were differentially expressed (1.5-fold change, Benjamini-Hochberg corrected q-value of 1x10
-4). We hypothesized that many of these markers would be shared in an independent UPJO cohort with renal damage and low function, reflecting common processes in renal damage, whereas other markers would be unique to PN-RS. Of the 820 markers discriminating ‘scar’ from ‘no scar’, a total of 570 were shared in the UPJO cohort, leaving 250 SCAMPs that were unique to PN-RS. Receiver-operator characteristic curves were determined for select markers. These ranged up to 0.96 AUC for individual markers, highlighting the potential diagnostic capability of these markers after validation in larger cohorts. Ingenuity Pathway Analysis (IPA) (QIAGEN, Germany) was employed to determine the enriched functional categories of the 250 SCAMPs. SCAMPs reflect an activated immune response and are enriched in proteins related to neutrophil degranulation (z-score 5.7, p-value 3.2x10
-18) and antibacterial response (z-score 2.0, p-value 7.3x10
-19). TLR4 (z-score = 4.4, p-value = 2.3x10
-19) was predicted to be a master regulator of SCAMPs. In comparison with the animal model of PN, each of the top 12 SCAMPs exhibited a striking degree of co-regulation between the human urine samples and the animal model, supporting the applicability of the model to mirror the underlying biological factors present in the human condition.
Numerous highly significant upstream regulators were shared between the human identified SCAMPs and the animal model. These included LPS, TGFB1, TNF, and several others related to immune response and activation of TLR4.
Conclusions The urinary proteome contains potential diagnostic markers of pyelonephritic renal scarring that are distinct from other causes of renal damage. Human and animal studies of renal scarring converge to identify a set of putative urinary markers and upstream regulators of scarring. Additional larger cohort studies are needed to validate these markers.
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