Kidney Injury Molecule-1 and Periostin Urinary Excretion and Tissue Expression Levels and Association with Glomerular Disease Outcomes

Abstract

<b><i>Introductions:</i></b> Kidney injury molecule-1 (KIM-1) and periostin (POSTN) are proximal and distal tubule injury biomarkers. We tested whether baseline urine KIM-1/Cr (uKIM-1/Cr) and/or uPOSTN/Cr correlated with disease severity or improved a remission prediction model. <b><i>Methods:</i></b> Baseline uKIM-1/Cr and uPOSTN/Cr were measured on spot urine samples from immunosuppression-free patients enrolled in Nephrotic Syndrome Study Network until December 15, 2014. Urine protein/Cr (UPCR) and albumin/Cr (UACR) were measured at baseline, 4 months, and until last follow-up. Glomerular and tubulointerstitial (TI) expression arrays were analyzed from a baseline research renal biopsy core collected during a clinically indicated biopsy. Renal diagnoses were centrally confirmed, sections scanned, and measured morphometrically. Correlations between baseline uKIM-1/Cr and uPOSTN/Cr and UPCR, UACR, histopathologic features, glomerular and TI KIM-1 and POSTN expression levels, and renal outcomes were assessed. <b><i>Results:</i></b> Baseline uKIM-1/cr correlated with UPCR and UACR and were associated with complete remission (CR) after adjustment for proteinuria, histopathologic diagnosis, and treatment. Baseline uKIM-1/Cr also correlated with degree of foot process effacement and acute tubular injury. Glomerular and TI KIM-1 expression levels correlated with UPCR and UACR. Higher TI KIM-1 expression levels correlated with interstitial fibrosis, tubular atrophy, and global glomerulosclerosis, while glomerular KIM-1 expression correlated with time to remission. Findings for POSTN were of lesser statistical strength. <b><i>Discussion/Conclusion:</i></b> Lower baseline uKIM-1/Cr values were associated with more rapid time to CR after adjusting for proteinuria, histopathologic diagnosis, and treatment. Increased TI KIM-1 expression levels in proteinuric states were associated with chronic morphological injury; lower glomerular expression levels were associated with a greater potential for proteinuria reversibility.

Serum Protein Exposure Activates a Core Regulatory Program Driving Human Proximal Tubule Injury

“…For the first time, we detail the epigenomic regulation of HAVCR1 , a key kidney injury biomarker gene. HAVCR1 is also upregulated in patients with FSGS versus patients with MCD and this correlates with increased shedding of HAVCR1 protein into the urine of these patients 70 and in our 3D MPS tubule cells exposed to serum. A maladaptive consequence of AKI can be ECM remodeling resulting in interstitial fibrosis.…”

Calcium oxalate crystal-induced secretome derived from proximal tubular cells, not that from distal tubular cells, induces renal fibroblast activation

“…Additionally, each tubular segment secretes different biomarkers, which can be detected in the urine and be used to localize the injury site [ 57 ]. For instance, the increased urinary level of kidney injury molecule-1 (KIM-1), a marker for proximal tubular injury, is associated with acute kidney injury (AKI) and CKD development [ 58 ].…”

Rationale and design of the Nephrotic Syndrome Study Network (NEPTUNE) Match in glomerular diseases: designing the right trial for the right patient, today

“… 17 - 19 Blood- and urine-derived noninvasive proteomic and metabolomic biomarker profiles are mapped to transcriptomic signatures in the kidney. 16 , 20 - 23 The heterogeneous information sources are carefully annotated in the NEPTUNE Knowledge Network for comprehensive mechanistic disease definitions. The NEPTUNE Knowledge Network is accessed by the kidney research community via a study-specific NEPTUNE tranSMART instance.…”