The distinction at the heart of the debate is between functional and intrinsic AKI. A child whose kidney function has dropped mainly because of reduced renal perfusion may respond well to restoration of circulating volume and careful hemodynamic optimization. Apply the same fluid-driven approach to a child with established intrinsic kidney injury and accumulating fluid, however, and the intervention may do more harm than good. Unfortunately, telling these two situations apart early is far from straightforward, especially in infants and children, in whom baseline creatinine is often unknown, urine output can be difficult to measure accurately, and multiple mechanisms of injury frequently coexist in the same patient.

Writing in the same issue of Pediatric Research, Akash Deep of King’s College Hospital in London examines a new study by Feinauer and colleagues that tested whether urinary tissue inhibitor of metalloproteinases-2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7) could solve this diagnostic dilemma. The researchers studied 179 neonates and children, including 76 with AKI, of whom 22 were classified as having functional AKI and 54 as having intrinsic AKI. The product of the two urinary biomarker concentrations, written as [TIMP-2]×[IGFBP7], was compared against urinary calprotectin, fractional excretion of sodium (FENa) and the urinary protein-to-creatinine ratio. The results were revealing. The TIMP-2 and IGFBP7 product performed reasonably well at identifying AKI overall, with an area under the receiver operating characteristic curve (AUC) of 0.76, but its ability to separate functional from intrinsic AKI was considerably more modest, at an AUC of 0.68. Calprotectin did better, achieving an AUC of 0.85, while the humble urinary protein-to-creatinine ratio delivered the best discrimination of all, at 0.89. FENa, despite its long-standing clinical use for exactly this purpose, managed only 0.72.

Perhaps none of this should come as a surprise, because it reflects a fundamental mismatch between what these biomarkers were built to do and what the study asked of them. TIMP-2 and IGFBP7 are markers of tubular cell stress and cell-cycle arrest. They were developed principally to identify a kidney at risk of developing AKI, not to establish the anatomical or pathophysiological cause of injury that has already occurred. A stressed tubular cell is not necessarily an irreversibly damaged tubular cell, and cellular stress may appear during hemodynamic disturbance well before conventional evidence of intrinsic kidney injury shows up. Asking [TIMP-2]×[IGFBP7] to distinguish functional from structural AKI may therefore be asking the biomarker a fundamentally different question from the one it was designed to answer, and the modest AUC reflects that mismatch rather than a failure of the biomarker itself.

The distinction matters enormously as the field moves toward more precise phenotyping of AKI. Serum creatinine and urine output predominantly report on kidney function. TIMP-2 and IGFBP7 provide information about cellular stress. Other biomarkers, including neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1), reflect different aspects of tubular injury, while calprotectin may offer a window into intrarenal inflammation. Proteinuria, though far less novel, can signal glomerular and tubular damage. Crucially, these markers are not competitors vying to replace one another; they measure different components of the broad syndrome that clinicians lump together under the single label of AKI. The search for a renal equivalent of troponin, the cardiac protein that revolutionized the diagnosis of heart attacks, has been seductive, but AKI is not one disease, and no single molecule is likely to capture its full complexity.

The new study also calls into question the traditional binary division of AKI into functional and intrinsic disease. This distinction is clinically useful, but kidney injury in critically ill children rarely obeys such tidy categories. AKI evolves over time: a child may begin with reduced renal perfusion and no significant structural injury, progress through a phase of tubular cellular stress, and, if the insult persists, go on to develop established tubular damage. In sepsis, cardiac disease and liver failure, hemodynamic, inflammatory and microcirculatory mechanisms may all operate simultaneously. At the bedside, functional and intrinsic AKI may therefore represent points along a continuum rather than two completely separate entities. Recent pediatric consensus recommendations have reached a similar conclusion, emphasizing AKI phenotyping and the need to move beyond a purely functional definition based on creatinine and urine output.

Timing, too, emerges as a critical variable. In the Feinauer study, urine samples were obtained only after AKI had already been diagnosed, and the biomarkers were measured at a single time point. The intrinsic AKI group also contained a higher proportion of patients with moderate-to-severe AKI when KDIGO stages 2 and 3 were considered together. Higher biomarker concentrations could therefore reflect, at least in part, the severity or duration of kidney injury at the moment of sampling rather than its original mechanism. Serial measurements beginning before, or very early in, the evolution of AKI would offer a far better picture of how stress and damage biomarkers change as functional impairment progresses to established injury, and could potentially allow clinicians to intervene during the reversible phase.

One finding in particular deserves attention, and it is the study’s most humbling. The urinary protein-to-creatinine ratio, a cheap and widely available investigation available in virtually every hospital laboratory, provided the best discrimination between functional and intrinsic AKI, outperforming every novel biomarker tested. Novelty, in other words, does not necessarily translate into greater clinical value. Before any new biomarker is introduced into routine practice, the field needs to demonstrate that it adds genuinely useful information to careful clinical assessment and inexpensive laboratory tests already in hand. That said, the commentary cautions against concluding that proteinuria alone can settle the question. The number of children with functional AKI in the study was small, the population ranged from neonates to adolescents, an age span over which renal physiology changes substantially, and several clinically important forms of functional AKI, including hepatorenal syndrome and congestive cardiorenal syndrome, were excluded. The definition of functional AKI was also necessarily retrospective, depending partly on response to fluid resuscitation or recovery of renal function within 72 hours. Although classification was performed independently by three clinicians with good agreement, the absence of a reliable reference standard remains one of the biggest obstacles facing AKI biomarker research.

The more promising path forward may lie in combining biomarkers with clinical context rather than using them in isolation. The Acute Disease Quality Initiative consensus has recommended pairing functional and damage biomarkers to improve diagnostic precision, and pediatric studies have shown that biomarker-defined phenotypes can provide prognostic information beyond serum creatinine alone. A prospective study of 134 critically ill children with AKI by Hui and colleagues illustrates the point vividly: urinary NGAL, TIMP-2, IGFBP7 and CCL14, assessed individually and serially, provided only moderate discrimination for persistent and prolonged AKI, but combining biomarker concentrations with the concurrent AKI stage substantially improved predictive performance. For bedside practice, that is the comparison that matters, because biological information appears to add the most value when interpreted alongside what clinicians already know about the patient, including underlying disease, hemodynamics, fluid balance, nephrotoxic exposure, creatinine trajectory and urine output.

The next step, the commentary argues, should be more than another round of AUC comparisons. Better discrimination is useful, but it does not by itself establish clinical utility. The decisive question is whether a biomarker result changes what clinicians actually do: does it influence fluid administration or de-resuscitation, nephrotoxin exposure, hemodynamic management or drug dosing? Can it identify children who need earlier nephrology involvement or closer follow-up after an episode of AKI? Ultimately, does biomarker-guided management improve kidney recovery or patient-centered outcomes? Prospective multicenter studies with serial measurements will be essential, describing how phenotype changes over time and whether the transition from stress to injury can be caught before serum creatinine betrays it. Some researchers have even proposed that biomarkers could eventually become theragnostic, not only identifying disease but helping to guide therapy as their concentrations shift in response to treatment. The study by Feinauer and colleagues is valuable not because it delivers a new stand-alone test for intrinsic AKI, but because it forces the field to be explicit about what it expects from a biomarker. Detecting kidney stress, demonstrating structural injury, measuring loss of function and identifying the cause of AKI are different tasks, and the future of AKI diagnosis will almost certainly involve combining clinical assessment, risk stratification tools, kidney function and selected markers of stress and damage. The challenge now is to determine which combinations genuinely change management and improve both short- and long-term outcomes for the child in front of us.

Subject of Research: Biomarkers for distinguishing functional from intrinsic acute kidney injury in critically ill children

Article Title: Beyond diagnosing acute kidney injury: defining what we need from kidney biomarkers

Article References: Deep, A. (2026). Beyond diagnosing acute kidney injury: defining what we need from kidney biomarkers. Pediatric Research. https://doi.org/10.1038/s41390-026-05540-0

Image Credits: AI Generated

DOI: 10.1038/s41390-026-05540-0

Keywords: acute kidney injury, biomarkers, TIMP-2, IGFBP7, calprotectin, serum creatinine, pediatric intensive care, proteinuria, NGAL, AKI phenotyping, tubular stress, precision medicine

The investigation began in the clinic. The researchers measured serum IGFBP7 levels in patients with sepsis admitted to the Second Affiliated Hospital of Anhui Medical University and compared them with healthy controls. The results were striking: patients with sepsis showed markedly elevated circulating IGFBP7, and those levels correlated positively with serum creatinine, blood urea nitrogen, alanine aminotransferase, and aspartate aminotransferase, the standard laboratory markers of kidney and liver dysfunction. In other words, the more IGFBP7 a patient carried in their bloodstream, the worse their organs appeared to be faring. This clinical signal set the stage for a deeper mechanistic dive using animal models.

Turning to mice, the team used the cecal ligation and puncture model, a widely used experimental simulation of septic shock in which the cecum is perforated to release fecal bacteria into the abdominal cavity. As in humans, IGFBP7 surged in the serum and urine of septic mice, and Western blot analysis revealed upregulation of the protein in the kidneys, liver, and lungs. Immunofluorescence staining pinpointed the cellular sources: proximal tubular epithelial cells in the kidney and hepatocytes in the liver. Cultured mouse tubular epithelial cells and hepatocytes exposed to lipopolysaccharide, the toxic component of bacterial outer membranes, likewise ramped up IGFBP7 production, confirming that the response is cell-autonomous rather than a secondary artifact of systemic illness.

The decisive experiment came from genetics. The researchers generated mice lacking the Igfbp7 gene entirely, as well as organ-specific knockout lines in which the gene was deleted only in renal tubular epithelial cells or only in hepatocytes. When subjected to sepsis, the global knockout mice survived at significantly higher rates than their wild-type littermates. Their kidneys, livers, and lungs showed dramatically less injury: lower creatinine and BUN, reduced liver enzymes, less alveolar septal thickening and capillary congestion in the lungs, and blunted activation of NF-κB, the master transcriptional switch of inflammation. Proinflammatory cytokines such as tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-6 were all substantially tamped down. The tissue-specific knockouts confirmed that IGFBP7 acts locally within each organ, not merely as a circulating signal.

To understand how a secreted binding protein could wreak such havoc inside cells, the team performed an unbiased proteomic hunt. Using co-immunoprecipitation followed by liquid chromatography-tandem mass spectrometry, they pulled down proteins that physically associate with IGFBP7 in septic kidney tissue. The top candidate was oxoglutarate dehydrogenase, or OGDH, a critical enzyme in the tricarboxylic acid cycle that catalyzes the conversion of alpha-ketoglutarate to succinyl-CoA, a direct precursor of succinate. The interaction was confirmed in the kidneys, liver, and lungs of septic mice, and high-resolution confocal microscopy showed IGFBP7 and OGDH co-localizing inside stressed cells. Subcellular fractionation revealed that IGFBP7, though classically considered a secreted protein, can be internalized by cells and detected in the mitochondrial fraction where OGDH resides. Molecular docking and truncation experiments mapped the binding interface to the Kazal-like and immunoglobulin-like C2-type domains of IGFBP7.

The functional consequences of this interaction proved to be a story about a chemical modification called lysine succinylation. Succinyl-CoA can covalently attach succinate groups to lysine residues on target proteins, altering their conformation and activity, and the mitochondrial enzyme SIRT5 normally acts as a desuccinylase that keeps this modification in check. The researchers found that during sepsis, the association between OGDH and SIRT5 was weakened, and IGFBP7 overexpression further disrupted this partnership. The result was a marked increase in overall OGDH succinylation, which coincided with enhanced OGDH enzymatic activity and a flood of succinate in the serum and kidney tissue. Consistent with this chain of events, serum succinate levels in mice correlated positively with IGFBP7, creatinine, ALT, and interleukin-1 beta, tying the metabolic shift directly to organ injury and inflammation.

Causality was tested in both directions. First, the team showed that succinyl phosphonate, a specific inhibitor of OGDH, reduced the expression of the kidney injury marker KIM-1 and NF-κB phosphorylation in stressed cells, implicating OGDH activity in the damage pathway. Second, and more compellingly, they administered dimethyl succinate, a cell-permeable succinate ester, to Igfbp7 knockout mice undergoing sepsis. Restoring succinate levels largely erased the protective phenotype: kidney and liver function markers climbed, tubular injury and macrophage infiltration worsened, and lung dysfunction partially returned. A parallel rescue in cultured cells produced the same outcome. Together, these experiments establish succinate accumulation as a critical downstream mediator through which IGFBP7 inflicts its damage.

The downstream target of all this succinate is the mitochondrion itself. Excessive succinate is known to disrupt redox balance, drive reactive oxygen species production through complex II of the electron transport chain, and destabilize HIF-1 alpha to amplify interleukin-1 beta expression. In this study, lipopolysaccharide-treated cells with high IGFBP7 showed depressed oxygen consumption, depleted ATP, reduced mitochondrial DNA copy number, fragmented and rounded mitochondria, collapsed membrane potential, and oxidative stress. Silencing Igfbp7 reversed essentially all of these defects, restoring elongated mitochondrial networks, membrane potential, and energy production. In septic mice, Igfbp7 deficiency preserved mitochondrial ultrastructure as visualized by transmission electron microscopy, rebalanced fission and fusion protein expression, and reduced oxidative damage markers across the kidneys, liver, and lungs.

Perhaps the most clinically exciting finding is that the damage is pharmacologically reversible. A neutralizing antibody against IGFBP7, administered immediately after sepsis induction and again twelve hours later, lowered circulating IGFBP7 and succinate, reduced inflammatory cytokines, and significantly improved kidney, liver, and lung function in septic mice. Tissue histology showed less injury and fewer infiltrating macrophages in all three organs, and mitochondrial dynamics and biogenesis markers in the kidney normalized. The treatment also attenuated senescence-associated changes, reducing p16 and p21 expression and senescence-associated beta-galactosidase activity in renal tissue, consistent with IGFBP7’s established role as a component of the senescence-associated secretory phenotype.

The authors are careful to note the limitations. The evidence rests primarily on young male mice and a small clinical cohort, the cecal ligation and puncture model cannot fully capture the heterogeneity of human sepsis, and the precise lysine residues on OGDH whose succinylation drives its hyperactivity remain unidentified. How IGFBP7 enters cells and reaches the mitochondrial compartment is also unresolved. Still, the study delivers a coherent and testable model: sepsis elevates IGFBP7, which penetrates cells and displaces SIRT5 from OGDH, unleashing succinate production that poisons mitochondria and ignites inflammatory injury across multiple organs. With IGFBP7 inhibitors already under investigation for kidney disease and fibrosis, the prospect of translating this axis into a therapy for sepsis-induced multiple organ dysfunction no longer seems remote, and a protein once regarded as a mere biomarker may soon become a treatment target in one of medicine’s most urgent battles.

Subject of Research: The role of IGFBP7 and OGDH-mediated succinate accumulation in sepsis-induced multiple organ dysfunction

Article Title: IGFBP7 promotes sepsis-induced multiple organ dysfunction by enhancing OGDH-mediated succinate accumulation

Article References: Xie, S.-S., Dong, Y.-H., Xu, L., Dong, Z.-H., Gao, Y.-Y., Li, W., Ma, W.-X., Ru, Y.-X., Zhao, T., Hou, R., Zhang, L.-X., Yang, Q., Jin, J., Wen, J.-G., & Meng, X.-M. (2026). IGFBP7 promotes sepsis-induced multiple organ dysfunction by enhancing OGDH-mediated succinate accumulation. Journal of Advanced Research. https://doi.org/10.1016/j.jare.2026.09.013

Image Credits: AI Generated

DOI: 10.1016/j.jare.2026.09.013

Keywords: sepsis, IGFBP7, OGDH, succinate, mitochondrial dysfunction, multiple organ dysfunction syndrome, SIRT5, succinylation, inflammation, NF-kB, acute kidney injury, therapeutic target