Prasad Devarajan

OBJECTIVES: To test whether urine olfactomedin 4 (uOLFM4) can predict furosemide responsiveness in patients at high risk for acute kidney injury (AKI) early in the PICU course. A secondary outcome was prediction of kidney replacement therapy (KRT) initiation in this cohort. DESIGN: Prospective observational cohort study. SETTING: Two quaternary care PICUs. PATIENTS: Two hundred forty PICU patients with a renal angina index greater than or equal to 8 and a urine sample collected on PICU days 0–1. Fifty-six patients received a furosemide dose on PICU days 1–4 and 44 received KRT. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: uOLFM4 was measured via enzyme-linked immunosorbent assay. Urine neutrophil gelatinase-associated lipocalin (uNGAL) was measured via particle-enhanced turbidimetric immunoassay by the clinical laboratory. We compared groups using Mann-Whitney U tests or Kruskal-Wallis tests and calculated area under the receiver operating characteristic curve for performance of uOLFM4 and uNGAL to predict furosemide responsiveness on PICU days 1–4 and KRT receipt. Median (interquartile range) uOLFM4 and uNGAL concentrations were higher in patients who were furosemide nonresponsive (uOLFM4 694 ng/mL [214–1478 ng/mL] vs. 139 ng/mL [46–529 ng/mL]; p = 0.0004 and uNGAL 1149 ng/mL [204–2284 ng/mL] vs. 53 ng/mL [50–1533 ng/mL]; p = 0.0076) and higher in patients who received KRT. uOLFM4 and uNGAL had similar moderate discriminatory ability to predict furosemide responsiveness (area under the curve, 0.77 [95% CI, 0.65–0.90]; p = 0.0005 and 0.71 [95% CI, 0.57–0.85]; p = 0.0088, respectively). uOLFM4 of 156 ng/mL had 59% sensitivity, 96% specificity, a positive predictive value of 64%, and negative predictive value (NPV) of 95% to predict furosemide responsiveness. CONCLUSIONS: In critically ill children at high risk for AKI, both uOLFM4 and uNGAL have moderate discriminatory ability to predict furosemide responsiveness and KRT receipt on the first day of PICU stay. The NPV greater than or equal to 95% for uOLFM4 for both outcomes make it a promising candidate for implementation into clinical decision support to facilitate early KRT initiation decision-making.

Objective: To evaluate the ability of the Renal Activity Index for Lupus (RAIL) score, a urine biomarker-derived score, to capture and predict the course of active lupus nephritis (LN) in adult patients. Methods: Available serial urine samples collected up to week 52 from a subset of adults with active biopsy-proven proliferative LN participating in the double-blind randomized ALLURE trial of abatacept ( ClinicalTrials.gov : NCT01714817 ) were used to calculate RAIL scores from creatinine-adjusted urine biomarkers (neutrophil gelatinase-associated lipocalin [NGAL], kidney injury molecule 1 [KIM-1], monocyte chemotactic protein 1 [MCP-1], adiponectin, hemopexin, ceruloplasmin). Discriminative performance of RAIL scores alone over time were compared with urine protein/creatinine ratio (UPCR), kidney function (estimated glomerular filtration rate [eGFR]), and mixed model analysis of RAIL score adjusted for baseline UPCR, eGFR, age, weight, sex, and race, with comparisons by renal response states including complete renal response (CRR), partial renal response but not CRR (PRR-only), and nonresponse (NR). Results: The analysis included 240 patients who contributed 599 samples. At weeks 12/24/52, there were 44/22/15 patients with PRR-only, 27/33/18 with CRR, and 127/61/15 NR. RAIL scores, eGFR, and UPCR improved over time irrespective of abatacept use, but were significantly lower with CRR compared to NR. The eGFR alone had poor accuracy (area under the receiver-operating characteristic curve [AUC] < 0.51) to discriminate renal response. Only after correction of baseline UPCR and eGFR, the RAIL score had excellent accuracy to reflect CRR from other renal response states at the current (AUC = 0.83-0.84) and next visit (AUC = 0.84-0.85) and performed better than UPCR; without correction, UPCR and RAIL score had similarly good accuracy. Conclusion: RAIL scores identify active LN and longitudinally predict the course of adult LN. ( ClinicalTrials.gov : NCT01714817 )

Our findings identify a reliable timepoint at which female mice subjected to unilateral ischemia-reperfusion consistently develop CKD changes relative to much shorter duration in male mice. We provide a novel model to study the AKI-CKD transition in female mice.

Fibrosis is a common outcome of numerous pathologies, including chronic kidney disease (CKD), a progressive renal function deterioration. Current approaches to target activated fibroblasts, key effector contributors to fibrotic tissue remodeling, lack specificity. Here, we report Gucy1α1 as a specific kidney fibroblast marker. Gucy1α1 levels significantly increased over the course of two clinically relevant murine CKD models and directly correlated with established fibrosis markers. Immunofluorescent (IF) imaging showed that Gucy1α1 comprehensively labelled cortical and medullary quiescent and activated fibroblasts in the control kidney and throughout injury progression, respectively. Unlike traditionally used markers platelet derived growth factor receptor beta (Pdgfrβ) and vimentin (Vim), Gucy1α1 did not overlap with off-target populations such as podocytes. Notably, Gucy1α1 labelled kidney fibroblasts in both male and female mice. Furthermore, we observed elevated GUCY1α1 expression in the human fibrotic kidney and lung. Studies in the murine models of cardiac and liver fibrosis revealed Gucy1α1 elevation in activated Pdgfrβ-, Vim- and alpha smooth muscle actin (αSma)-expressing fibroblasts paralleling injury progression and resolution. Overall, we demonstrate Gucy1α1 as an exclusive fibroblast marker in both sexes. Due to its multiorgan translational potential, GUCY1α1 might provide a novel promising strategy to specifically target and mechanistically examine fibroblasts.

Introduction: Early and accurate diagnosis of urinary tract infection (UTI) can prevent serious sequelae including chronic kidney disease. Multiple individual studies have identified urine neutrophil gelatinase-associated lipocalin (uNGAL) as a promising biomarker for early diagnosis of UTI. We sought to understand the distribution and diagnostic accuracy of uNGAL values in patients presenting with UTI symptoms.Methods: Our systematic literature reviews in PubMed, Embase, and Cochrane Reviews up to March 2024, identified 25 studies reporting mean/median, standard deviation/quartiles, and detection limits of uNGAL in symptomatic patients with and without culture-confirmed UTI. Seventeen studies were in children. Meta-analyses were performed using the quantile estimation (QE) method estimating the distributions of uNGAL, which were then compared between the UTI and non-UTI groups for identifying the best cut-off points maximizing the Youden index. Sensitivity analyses were performed on all 25 studies including adult patients.Results: We found that uNGAL levels were significantly higher in samples with confirmed UTI compared to those without. In pediatric studies, median and 95% confidence interval (CI) of uNGAL values were 22.41 (95% CI of 9.94, 50.54) ng/mL in non-UTI group vs. 118.85 (95% CI of 43.07, 327.97) ng/mL in UTI group. We estimated the cut-off point of 48.43 ng/mL with highest sensitivity (96%) and specificity (97%) in children. Sensitivity analysis including both pediatric and adult studies yielded similar results.Discussion: The level of uNGAL in symptomatic patients with confirmed UTI is much higher than that reported in patients without UTI. It may be used as a diagnostic tool to identify UTI early among symptomatic patients. The range of uNGAL concentrations and cut-off points reported in subjects with UTI is much lower than that reported in patients with acute intrinsic kidney injury.Systematic Review Registration: https://www.crd.york.ac.uk/, PROSPERO (CRD42023370451).

Fibrosis is a common outcome of numerous pathologies, including chronic kidney disease (CKD), a progressive renal function deterioration. Current approaches to target activated fibroblasts, key effector contributors to fibrotic tissue remodeling, lack specificity. Here, we report Gucy1α1 as a specific kidney fibroblast marker. Gucy1α1 levels significantly increased over the course of two clinically relevant murine CKD models and directly correlated with established fibrosis markers. Immunofluorescent (IF) imaging showed that Gucy1α1 comprehensively labelled cortical and medullary quiescent and activated fibroblasts in the control kidney and throughout injury progression, respectively. Unlike traditionally used markers platelet derived growth factor receptor beta (Pdgfrβ) and vimentin (Vim), Gucy1α1 did not overlap with off-target populations such as podocytes. Notably, Gucy1α1 labelled kidney fibroblasts in both male and female mice. Furthermore, we observed elevated GUCY1α1 expression in the human fibrotic kidney and lung. Studies in the murine models of cardiac and liver fibrosis revealed Gucy1α1 elevation in activated Pdgfrβ-, Vim- and alpha smooth muscle actin (αSma)-expressing fibroblasts paralleling injury progression and resolution. Overall, we demonstrate Gucy1α1 as an exclusive fibroblast marker in both sexes. Due to its multiorgan translational potential, GUCY1α1 might provide a novel promising strategy to specifically target and mechanistically examine fibroblasts.

Examining kidney fibrosis is crucial for mechanistic understanding and developing targeted strategies against chronic kidney disease (CKD). Persistent fibroblast activation and tubular epithelial cell (TEC) injury are key CKD contributors. However, cellular and transcriptional landscapes of CKD and specific activated kidney fibroblast clusters remain elusive. Here, we analyzed single cell transcriptomic profiles of two clinically relevant kidney fibrosis models which induced robust kidney parenchymal remodeling. We dissected the molecular and cellular landscapes of kidney stroma and newly identified three distinctive fibroblast clusters with “secretory”, “contractile” and “vascular” transcriptional enrichments. Also, both injuries generated failed repair TECs (frTECs) characterized by decline of mature epithelial markers and elevation of stromal and injury markers. Notably, frTECs shared transcriptional identity with distal nephron segments of the embryonic kidney. Moreover, we identified that both models exhibited robust and previously unrecognized distal spatial pattern of TEC injury, outlined by persistent elevation of renal TEC injury markers including Krt8 and Vcam1, while the surviving proximal tubules (PTs) showed restored transcriptional signature. We also found that long-term kidney injuries activated a prominent nephrogenic signature, including Sox4 and Hox gene elevation, which prevailed in the distal tubular segments. Our findings might advance understanding of and targeted intervention in fibrotic kidney disease.

Acute kidney injury (AKI) is a major risk factor for long-term adverse outcomes, including chronic kidney disease. In mouse models of AKI, maladaptive repair of the injured proximal tubule (PT) prevents complete tissue recovery. However, evidence for PT maladaptation and its etiological relationship with complications of AKI is lacking in humans. We performed single-nucleus RNA sequencing of 120,985 nuclei in kidneys from 17 participants with AKI and seven healthy controls from the Kidney Precision Medicine Project. Maladaptive PT cells, which exhibited transcriptomic features of dedifferentiation and enrichment in pro-inflammatory and profibrotic pathways, were present in participants with AKI of diverse etiologies. To develop plasma markers of PT maladaptation, we analyzed the plasma proteome in two independent cohorts of patients undergoing cardiac surgery and a cohort of marathon runners, linked it to the transcriptomic signatures associated with maladaptive PT, and identified nine proteins whose genes were specifically up- or down-regulated by maladaptive PT. After cardiac surgery, both cohorts of patients had increased transforming growth factor–β2 (TGFB2), collagen type XXIII-α1 (COL23A1), and X-linked neuroligin 4 (NLGN4X) and had decreased plasminogen (PLG), ectonucleotide pyrophosphatase/phosphodiesterase 6 (ENPP6), and protein C (PROC). Similar changes were observed in marathon runners with exercise-associated kidney injury. Postoperative changes in these markers were associated with AKI progression in adults after cardiac surgery and post-AKI kidney atrophy in mouse models of ischemia-reperfusion injury and toxic injury. Our results demonstrate the feasibility of a multiomics approach to discovering noninvasive markers and associating PT maladaptation with adverse clinical outcomes.