Lactate in acute kidney injury: pathobiology, risk stratification, and clinical interpretation

Abstract

Lactate is frequently measured in patients with acute kidney injury (AKI), but its interpretation remains challenging because circulating lactate reflects systemic metabolic stress rather than kidney injury. Although elevated lactate levels are associated with adverse outcomes in critically ill patients with AKI, its biological and clinical significance varies according to disease context, timing, and the clinical question being addressed. This structured expert narrative review integrates mechanistic insights and clinical evidence to establish a context-dependent framework for interpreting lactate in AKI. We summarize the role of the kidney in lactate metabolism and discuss how impaired renal function, altered perfusion, mitochondrial dysfunction, and immune-metabolic remodeling contribute to lactate accumulation. We further evaluate clinical evidence regarding lactate in AKI risk assessment, severity evaluation, organ-support requirement, and mortality prediction, while emphasizing limitations related to confounding factors and clinical heterogeneity. Emerging clinical contexts, including extracorporeal membrane oxygenation-supported patients, are also considered. Overall, this framework supports a more precise interpretation of lactate as a context-dependent risk marker and metabolic signal rather than a kidney-specific biomarker.

Introduction

Acute kidney injury (AKI) is a common and clinically heterogeneous syndrome that is associated with prolonged hospitalization, increased healthcare burden, and worse renal and survival outcomes [1–3]. In routine practice, AKI is still identified and staged mainly by serum creatinine and urine output [4]. These measures remain essential, but they are far from ideal. Both may lag behind the underlying injury, and neither is particularly effective in capturing early biological change or distinguishing short-term risk at the time patients first present. This has sustained interest in additional markers that may improve early assessment and bedside risk evaluation [5–7].

Lactate is one of the most discussed candidates. At the bedside, it is usually interpreted as a marker of impaired perfusion, systemic stress, or metabolic disturbance [8–10]. In AKI, however, its significance is more complex. The kidney is not simply a bystander in lactate homeostasis; it is a major extrahepatic organ involved in lactate uptake, utilization, and gluconeogenesis [11–13]. When these functions are disrupted during AKI, lactate accumulation may, in some settings, partly reflect altered renal lactate handling and metabolic dysfunction rather than systemic illness alone [11–14]. Experimental work has added another dimension by suggesting that, in selected forms of AKI, lactate may also be linked to inflammatory signaling, immune regulation, and lactylation-related pathways involved in gene and protein regulation [15–19].

Taken together, these considerations make lactate difficult to interpret in AKI. The literature is highly heterogeneous with respect to patient population, sampling window, lactate-related index, endpoint definition, and clinical setting [20–22]. Most available data come from sepsis-associated AKI, critically ill patients receiving organ support, and selected perioperative cohorts, whereas evidence from emergency department and general ward populations remains much more limited [21–23]. Lactate in AKI therefore cannot be assumed to carry a uniform meaning across clinical scenarios [21,22].

This review approaches lactate in AKI as a context-dependent integrative signal rather than a kidney-specific biomarker. Our aim is not to assign lactate a single role across all AKI settings, but to clarify how its interpretation shifts with renal metabolic dysfunction, systemic illness severity, timing of measurement, and clinical context. We focus on three questions: why lactate rises in AKI, what lactate-related indices can realistically add to incident AKI risk assessment, severity or organ-support assessment, and mortality risk assessment after AKI diagnosis, and in which settings lactate is clinically informative, potentially misleading, or easily overinterpreted. This clinical interpretive framework is summarized in Figure 1.

Figure 1.

Bedside workflow for interpreting lactate in acute kidney injury. The workflow illustrates an endpoint-specific approach to lactate interpretation in AKI. Lactate should not be used alone to diagnose AKI, infer structural kidney injury, or determine renal recovery. Depending on the clinical question, lactate may support incident-AKI risk enrichment, assessment of illness severity or organ-support requirement after AKI develops, and short-term prognostic evaluation when interpreted together with kidney function, hemodynamics, illness severity, and treatment context. Lactate trends during CRRT or ECMO require consideration of extracorporeal effects and changes in systemic perfusion. A decline in circulating lactate reflects improved global lactate balance rather than renal recovery. Created in BioRender. Sun, Z. (2026) https://BioRender.com/8mz88ku.

Previous reviews have mainly focused on the association between lactate and clinical outcomes or on lactate-related renal metabolic mechanisms; however, an integrated framework linking renal lactate biology, clinical risk assessment, and context-specific interpretation of lactate in AKI remains limited. Compared with previous reviews that have addressed lactate metabolism, sepsis resuscitation, or AKI biomarkers separately, this review focuses on the specific interpretive problem that arises when hyperlactatemia and AKI coexist [8,9,12,13]. Its added value lies in linking renal lactate handling and gluconeogenesis, emerging evidence on immune-metabolic signaling and lactylation, and the interpretation of lactate-related indices across distinct clinical scenarios, including sepsis-associated AKI, perioperative AKI, CRRT, and extracorporeal membrane oxygenation (ECMO)-supported patients. We emphasize where lactate may support incident AKI risk assessment, post-AKI severity or organ-support assessment, and short-term mortality risk stratification, while clarifying where evidence remains insufficient or prone to overinterpretation.

Review design, literature identification, and evidence appraisal

This article was designed as a structured expert narrative review rather than a systematic review or meta-analysis. Its purpose was to synthesize mechanistic, translational, and clinical evidence relevant to the interpretation of lactate in acute kidney injury, with emphasis on renal lactate handling, lactate-related indices, clinical context, and the risk of overinterpretation.

PubMed, Embase, and Web of Science were searched from database inception to August 2026. Search terms combined AKI-related terms with lactate-related, clinical-setting, and mechanistic terms. The core strategy used combinations of the following terms: (“acute kidney injury” OR “AKI” OR “renal failure” OR “kidney dysfunction”) AND (“lactate” OR “hyperlactatemia” OR “lactate kinetics” OR “lactate clearance” OR “lactate trajectory” OR “lactate-to-albumin ratio”) AND (“prognosis” OR “mortality” OR “renal replacement therapy” OR “continuous renal replacement therapy” OR “CRRT” OR “sepsis” OR “septic shock” OR “critical illness” OR “cardiac surgery” OR “perioperative” OR “extracorporeal membrane oxygenation” OR “ECMO” OR “veno-arterial ECMO” OR “VA-ECMO” OR “veno-venous ECMO” OR “VV-ECMO” OR “extracorporeal cardiopulmonary resuscitation” OR “ECPR”). Additional searches used mechanistic terms including “renal gluconeogenesis”, “proximal tubular metabolism”, “mitochondrial dysfunction”, “metabolic reprogramming”, “inflammation”, “immune regulation”, and “lactylation”. Reference lists of key original studies and recent nephrology or critical care reviews were also screened.

Studies were considered relevant if they addressed lactate metabolism, lactate-related indices, AKI occurrence, AKI severity, organ support requirements, renal replacement therapy, or short-term outcomes in patients with AKI or populations at risk of AKI. Mechanistic and translational studies were included when they provided biologic plausibility for altered renal lactate handling, tubular metabolic dysfunction, inflammatory signaling, immune regulation, or lactylation-related pathways. Reports were not considered central to the synthesis if lactate was not directly assessed, AKI was not defined or was not clinically relevant to the analysis, lactate was reported only as a nonspecific component of illness severity without interpretable timing or association, or the report provided insufficient methodological detail to evaluate the lactate–AKI relationship. Studies focused exclusively on chronic kidney disease, inherited metabolic disorders, or non-clinical lactate biology without relevance to AKI interpretation were excluded from the main synthesis.

Study selection was performed by title and abstract screening, followed by full-text review of potentially relevant articles. Both authors participated in study selection and evidence interpretation, with differences resolved by discussion. Because this was an expert narrative synthesis rather than a systematic review, a PRISMA flow diagram, formal record counts, and item-by-item Prediction model Risk Of Bias ASsessment Tool (PROBAST) or Quality In Prognosis Studies (QUIPS) scoring were not generated. Accordingly, representative clinical studies were selected to cover the main AKI-relevant clinical settings and lactate-related indices, rather than to serve as an exhaustive catalog of all published associations. These studies were appraised qualitatively according to key methodological domains adapted from the methodological domains of PROBAST and QUIPS, including population characteristics, AKI definition, lactate measurement timing, endpoint definition, adjustment for confounding, validation status, model performance reporting, and clinical applicability [24,25]. Greater interpretive weight was given to studies with direct AKI relevance, clear lactate timing, multivariable adjustment, multicenter design, prospective design when available, internal or external validation, and reporting of discrimination or calibration. Quantitative pooling was not performed because of substantial heterogeneity in populations, settings, AKI definitions, lactate-related indices, timing windows, comparator models, and endpoints.

Physiological role of the kidney in lactate metabolism

Lactate is continuously produced under both aerobic and anaerobic conditions and should not be viewed simply as a byproduct of hypoxia. Circulating lactate levels reflect the balance among production, transport, utilization, and clearance [26–28]. Along with the liver, the kidney is a major extrahepatic organ involved in lactate uptake, utilization, and gluconeogenesis, and thus makes an important contribution to systemic lactate homeostasis [11–13].

This physiological role becomes especially relevant in AKI. Renal gluconeogenesis occurs mainly in proximal tubular cells, which are highly metabolically active and particularly vulnerable to injury [14,29,30]. When AKI develops, renal lactate uptake, utilization, and gluconeogenic conversion may all be impaired [12–14,30]. Elevated lactate in this setting does not reflect systemic stress or poor perfusion alone; it may also partly arise from disrupted renal metabolism [12–14].

Mechanisms of lactate dysregulation in AKI and potential injury-related pathways

Increased lactate production: ischemia, hypoxia, and enhanced glycolysis

Proximal tubular epithelial cells are among the most energy-demanding cells in the kidney. Under normal conditions, they rely mainly on fatty acid oxidation and oxidative phosphorylation for ATP production [29,31–33]. During AKI, however, impaired perfusion, microvascular dysfunction, and relative hypoxia limit oxidative metabolism and drive tubular cells toward glycolysis in order to maintain basic energy supply [14,31,34,35]. This shift favors the conversion of pyruvate to lactate and promotes lactate accumulation [32–34,36].

Legouis et al. combined renal arteriovenous catheterization in patients, lactate tolerance testing in mice, and glucose isotope tracing in rats, demonstrating impaired renal glucose production and lactate clearance during AKI together with suppression of proximal-tubular gluconeogenic programs [14]. Complementing these findings, Zager et al. demonstrated persistent renal cortical pyruvate depletion in ischemic and glycerol-induced AKI, with ischemia-associated lactate accumulation and reduced pyruvate dehydrogenase expression [35]. These findings support a shift away from oxidative and gluconeogenic metabolism toward a more glycolysis-dependent state, although they do not establish circulating lactate as a kidney-specific marker.

Reduced lactate clearance: impaired renal uptake, utilization, and gluconeogenic capacity

Elevated lactate in AKI cannot be explained by increased production alone [11,14,30]. Under physiological conditions, the kidney contributes to lactate clearance through uptake, utilization, and gluconeogenic conversion, particularly in proximal tubular cells [11–13,27]. Once AKI develops, these functions may be impaired by tubular injury, loss of metabolic integrity, and reduced gluconeogenic activity [12,14,29].

Human and experimental data suggest that AKI is associated with reduced renal lactate uptake, decreased renal glucose release, and downregulation of key gluconeogenic enzymes such as phosphoenolpyruvate carboxykinase 1 and fructose-1,6-bisphosphatase 1 [11,14,30]. These observations make reduced renal lactate clearance a biologically plausible component of hyperlactatemia in AKI [11–14]. In other words, lactate may rise not only because more is being produced, but also because the injured kidney is less able to use and convert it [13,14].

Mitochondrial dysfunction and metabolic reprogramming

Mitochondrial dysfunction and metabolic reprogramming are central to this process [32,37,38]. They not only contribute to tubular injury in AKI, but also help explain why increased lactate production and impaired lactate clearance can coexist [31,32,37,39]. Proximal tubular cells normally depend on intact mitochondrial oxidative metabolism, yet ischemic, septic, and nephrotoxic insults disrupt mitochondrial quality control, impair oxidative phosphorylation, and destabilize cellular energy homeostasis [31,37–40]. Under these conditions, tubular cells shift away from fatty acid oxidation and gluconeogenesis toward a more glycolysis-dependent state [14,31,32].

This metabolic shift may initially serve an adaptive purpose by helping stressed cells maintain short-term ATP supply. When sustained, however, it becomes maladaptive [32,34,37,39]. Reduced oxidative metabolism favors lactate generation, whereas suppression of gluconeogenesis and impaired lactate utilization limit its clearance [14,32,34,39]. Mitochondrial dysfunction and metabolic reprogramming therefore form a central metabolic axis in AKI, linking tubular injury to lactate accumulation and helping explain why elevated lactate may reflect more than a nonspecific stress signal in this setting [31,32,37–39].

Microcirculatory dysfunction, inflammation, and systemic stress as amplifiers

In severe AKI, particularly in the setting of sepsis or shock, disturbed lactate metabolism is further amplified by microcirculatory dysfunction, inflammatory activation, and systemic stress [41–43]. Even when global renal blood flow appears preserved, endothelial dysfunction, glycocalyx injury, oxidative stress, and coagulation abnormalities may create marked heterogeneity in renal microvascular perfusion [41–44]. This mismatch between macrocirculatory parameters and tissue-level oxygen delivery favors persistent metabolic stress and further lactate accumulation [41,42,44].

Taken together, these processes make lactate in severe AKI harder to interpret as a signal of tubular metabolism alone [41,42]. In severe illness, lactate elevation often reflects not a single mechanism but the combined effects of impaired microperfusion, inflammatory injury, and systemic physiological strain [8,10,41,42]. Microcirculatory dysfunction and systemic stress do not fully explain lactate in AKI, but they clearly amplify both metabolic imbalance and kidney injury [41–43].

Lactate and inflammatory amplification in AKI

In AKI, lactate may represent more than a marker of metabolic stress. Experimental and translational studies suggest that it can influence the local tissue environment, inflammatory signaling, and oxidative injury, potentially contributing to inflammatory amplification [16,45,46]. This supports a bidirectional view: ischemia, infection, and metabolic reprogramming increase lactate production, while lactate accumulation and the accompanying acidic milieu may in turn help sustain inflammatory activity and prolong tissue injury [45–47].

This perspective is particularly relevant in sepsis-associated AKI, where metabolic stress and inflammation are closely intertwined [16,21,23,45]. Lactate is not a direct measure of inflammation, but neither is it necessarily biologically inert [45,46]. In selected settings, it may function as a metabolically coupled signal that reflects, and may also help sustain, inflammatory injury [45–48].

Lactate and the immune microenvironment in AKI

Beyond inflammatory amplification, lactate may also influence the immune microenvironment in AKI [47,49–52]. Available mechanistic studies suggest effects on neutrophil activity and neutrophil extracellular trap formation, macrophage functional programs, and T-cell metabolism and trafficking [17,49,50,52]. These observations may be particularly relevant in sepsis-associated AKI, where persistent lactate elevation often coexists with immune dysregulation [21,23,49].

These immunoregulatory effects are unlikely to be uniform and probably vary with disease stage, tissue context, and the surrounding metabolic environment. Lactate therefore functions more plausibly as a context-sensitive modulator of immune behavior than as a simple immune activator or suppressor [49–52]. In AKI, this may be relevant to persistent inflammation, maladaptive repair, or both [47,49,53].

Lactylation and injury progression in AKI

Lactylation has broadened current thinking about how lactate may relate to kidney injury beyond its role as a metabolic marker [47,53]. Emerging studies suggest that lactate can influence chromatin state, gene transcription, and intracellular signaling through histone and non-histone lactylation, thereby linking metabolic disturbance to inflammatory signaling, mitochondrial dysfunction, and tubular injury [15,47,48,53,54].

In experimental models of AKI, lactylation-related pathways have been implicated in injury progression [17–19,54,55]. Histone H3K18 lactylation has been linked to inflammatory amplification in ischemia-reperfusion injury and sepsis-associated AKI, whereas non-histone lactylation has been associated with mitochondrial dysfunction, oxidative stress, and tubular injury through mechanisms involving proteins such as mitochondrial fission protein 1 (Fis1) and other metabolic regulators [15,18,19,54,55].

More direct study-level evidence has begun to define these pathways. Qiao et al. reported increased H3K18 lactylation in sepsis-associated AKI and linked this modification to activation of the RhoA/ROCK/Ezrin–NF-κB axis and aggravated renal injury [18]. Wei et al. showed that lactate-induced high mobility group box 1 lactylation in macrophages promoted neutrophil extracellular trap formation and worsened experimental SA-AKI [17]. In broader AKI models, Li et al. identified ALDH2 K52 lactylation as a contributor to mitochondrial dysfunction through PHB2 degradation and impaired mitophagy [19]. More recently, Huang et al. implicated an H3K18la–SPHK1–SIRT1 regulatory axis in lactate-enhanced tubular epithelial-cell pyroptosis in SA-AKI [55]. Collectively, these studies provide mechanistic support for pathway-specific mediator roles of lactate-derived lactylation, although the evidence remains predominantly experimental and cannot yet be translated into bedside lactate thresholds or treatment targets.

However, this evidence remains primarily mechanistic and translational. Current clinical lactate measurements reflect circulating lactate concentrations and cannot distinguish lactate as a metabolic substrate, a clearance-related marker, a systemic stress biomarker, or a lactylation-related signaling mediator. Therefore, lactylation provides biological plausibility for linking altered lactate metabolism to kidney injury progression, but it does not currently provide a sufficient basis for bedside lactate interpretation, AKI-specific risk stratification, or treatment decisions.

Translational interpretation: Marker, mediator, or both?

Current evidence supports a dual interpretation of lactate in AKI [12,16,21]. At the bedside, its principal value remains clinical rather than kidney-specific: lactate is most useful as an indicator of systemic stress, impaired perfusion, and overall illness severity. Its interpretation is therefore most appropriate when linked to a defined clinical question, such as incident AKI risk, post-AKI severity or organ-support assessment, or short-term mortality risk among patients with established AKI [8–10,12,21]. At the same time, mechanistic and translational studies suggest that, in selected contexts, lactate may also participate in injury progression through metabolic reprogramming, inflammatory amplification, immune modulation, and lactylation-related pathways [15–19,32,45,49]. The strongest support for this biologic role currently comes from experimental and translational work, especially in sepsis-associated AKI, rather than from direct clinical demonstration [15–19,21]. Thus, lactate in AKI is best understood primarily as a clinically useful marker of physiologic burden, while its potential mediator role remains most relevant to mechanistic interpretation and hypothesis generation [12,16,21]. Figure 2 provides an integrated mechanistic framework linking altered lactate production, impaired renal lactate handling, mitochondrial metabolic reprogramming, and emerging immune-metabolic signaling pathways in AKI.

Figure 2.

Integrated framework of lactate dysregulation and metabolic reprogramming in acute kidney injury. AKI-associated lactate dysregulation reflects an imbalance between lactate generation, utilization, and clearance. Upstream insults promote glycolytic activation and pyruvate-to-lactate conversion, while tubular dysfunction impairs renal lactate uptake, oxidation, and gluconeogenic capacity. These alterations are associated with mitochondrial dysfunction, metabolic reprogramming, and emerging inflammatory, immune, and lactate-related signaling pathways in experimental models. Clinically, lactate should be interpreted as an adjunctive indicator of systemic physiologic burden and short-term risk rather than a standalone marker of structural kidney injury or AKI-specific pathophysiology. Abbreviations: AKI, acute kidney injury; FAO, fatty acid oxidation; OXPHOS, oxidative phosphorylation; ROS, reactive oxygen species; PCK1, phosphoenolpyruvate carboxykinase 1; FBP1, fructose-1,6-bisphosphatase 1; NET, neutrophil extracellular trap. Created in BioRender. Sun, Z. (2026) https://BioRender.com/de323yn.

Clinical value of lactate-related indices across AKI-relevant clinical questions

Clinically, the central issue is not simply whether higher lactate is associated with worse outcomes, but what question the measurement is intended to answer: incident AKI risk, severity or organ-support requirement after AKI develops, or mortality risk among patients with established AKI [21,23,56]. Across the current literature, lactate-related indices appear to contribute mainly to earlier recognition of incident AKI risk in selected high-risk populations, assessment of illness severity or organ-support requirement after AKI develops, and short-term prognostic enrichment among patients with established AKI, especially in high-acuity settings such as sepsis-associated AKI, critical illness requiring organ support, and selected perioperative populations [21–23,56,57]. For a more structured overview, the main lactate-related indices in AKI-relevant settings are summarized in Table 1 according to their clinical context, target question, interpretive value, and major limitations.

Table 1.

Context-specific clinical use of lactate-related indices in acute kidney injury.

Index/measure	Main clinical setting	What it mainly reflects	Most useful role in AKI	Major limitation	Narrative assessment of evidence consistency and bedside readiness
Absolute lactate	ICU, sepsis-associated AKI, and other acute-care settings	Overall physiologic stress, impaired perfusion or oxygen utilization, adrenergic drive, and reduced metabolic clearance	Early risk enrichment and broad severity assessment	Highly context-dependent and influenced by shock, sepsis, hepatic dysfunction, drugs, catecholamine exposure, and renal dysfunction	Relatively consistent observational evidence; contextual interpretation only
Peak lactate or perioperative lactate burden	Cardiac surgery, major vascular surgery, and selected perioperative AKI settings	Cumulative perioperative stress and sustained hyperlactatemia during the intraoperative or early postoperative period	Perioperative risk enrichment and short-term prognostic assessment in selected high-risk surgical populations	Thresholds and sampling windows vary across studies and procedures; may reflect procedural complexity or hemodynamic instability rather than isolated renal injury	Relatively consistent evidence in selected perioperative cohorts
Conventionally defined lactate clearance / serial lactate change	Resuscitation phase, septic AKI, ICU, and CRRT-treated patients	Direction of physiologic change over time, including response to resuscitation and persistence or reversal of systemic stress	Dynamic monitoring and short-term prognostic assessment	Easily overinterpreted if detached from timing, treatment phase, or baseline lactate; does not directly indicate renal recovery or persistent renal hypoperfusion	Relatively consistent evidence in high-acuity settings; not an AKI-specific target
Serial lactate / lactate trajectory	ICU, sepsis-associated AKI, and heterogeneous critically ill AKI populations	Temporal pattern of physiologic derangement, including persistence, improvement, or late nonresolution	Longitudinal bedside interpretation and prognostic refinement	Requires repeated measurements and consistent sampling windows; trajectory patterns are less standardized and remain nonspecific	Emerging observational evidence; timing-dependent interpretation
Lactate-to-albumin ratio	Sepsis-associated AKI and critically ill ICU populations	Combined signal of hyperlactatemia and reduced physiologic reserve or inflammatory–nutritional burden	Risk stratification and mortality risk assessment when lactate alone may be insufficient	Albumin is influenced by inflammation, dilution, nutrition, and chronic illness; the ratio remains indirect and context-dependent	Limited context-specific evidence; broader validation needed
24-hour lactate / late persistent hyperlactatemia	Septic shock, prolonged ICU care, severe AKI, and CRRT populations	Ongoing metabolic stress, impaired clearance, and failure of lactate normalization over time	Identification of a persistently high-risk phenotype and adverse short-term prognosis	More reflective of persistent critical illness than isolated renal injury; thresholds and timing strategies are not uniform	Relatively consistent prognostic evidence; not standardized for AKI-specific use

Abbreviations. AKI: acute kidney injury; CRRT: continuous renal replacement therapy; ICU: intensive care unit.

Note. None of the lactate-related indices listed above is specific to kidney injury. In AKI, their clinical value lies primarily in contextual interpretation for risk stratification, severity assessment, prognostic evaluation, and monitoring, rather than in defining renal injury itself.

Explanatory footnote. The final column provides a narrative assessment rather than a formal GRADE or guideline evidence rating. The descriptors reflect the extent and consistency of AKI-relevant observational evidence, direct AKI relevance, confounding adjustment, model performance reporting, and external validation where available. They indicate potential value for adjunctive bedside interpretation, risk stratification, and prognostic assessment, not readiness for lactate-targeted therapy, AKI-specific treatment decisions, or standardized implementation. Persistent hyperlactatemia refers to failure of lactate to decline or normalize within a study-defined repeat-measurement window, often 6–24 h, rather than a uniform AKI-specific threshold.

Association between elevated lactate levels and the risk of AKI

Elevated lactate is associated with a higher risk of AKI across several high-risk settings, particularly in sepsis, critical illness, and major surgery [58–61]. For example, Fang et al. reported that lactate trajectories within 48 h after ICU admission were associated with AKI occurrence and hospital mortality in multicenter ICU cohorts, suggesting that serial lactate patterns may provide additional information on evolving systemic stress rather than kidney injury alone [62]. In these populations, lactate appears to capture not kidney injury in isolation but a broader physiologic state in which circulatory disturbance, inflammatory activation, and metabolic dysregulation converge and make AKI more likely [16,21,23,58].

This relationship is illustrated most clearly in sepsis-associated AKI, where elevated lactate has been independently linked to a greater likelihood of incident SA-AKI and where spline-based analyses suggest a sharper increase in risk once lactate approaches higher ranges [16,63]. A similar pattern has been reported outside sepsis: in critically ill patients with acute ischemic stroke, the risk of AKI increased progressively with rising lactate, and each 1 mmol/L increment was associated with a substantial increase in AKI risk [59]. Perioperative studies point in the same direction, particularly in cardiac and major vascular surgery, where intraoperative and early postoperative lactate burden has been associated with postoperative AKI [60,61,64]. Taken together, these studies support the view that lactate identifies a physiologic state in which AKI becomes more likely, rather than isolating renal injury itself [59–61,64].

Clinically, elevated lactate may refine early risk recognition in high-acuity populations by identifying systemic illness severity, circulatory stress, impaired oxygen utilization, or reduced metabolic reserve associated with AKI development or progression [21,58–61,64]. Representative clinical studies addressing incident AKI risk, AKI severity or organ-support requirement, and mortality risk among patients with AKI are systematically categorized and critically appraised in Table 2 [62,65].

Table 2.

Critical appraisal of representative clinical evidence on lactate-related indices in AKI settings.

Study	Setting and AKI definition	Lactate index	Main finding	Critical appraisal and AKI-specific interpretation
Fang et al., 2025 [62]	Multicenter ICU cohorts of patients with hyperlactatemia; AKI defined according to KDIGO serum creatinine criteria	48-h lactate trajectories after ICU admission	Lactate trajectories were associated with AKI and hospital mortality	Some methodological concern. Trajectory-based assessment requires repeated sampling and consistent timing. Lactate trajectories may refine AKI risk assessment but remain integrated markers of systemic illness severity and treatment response.
Bayar et al., 2019 [65]	Emergency department patients; AKI defined as serum creatinine >1.2 mg/dL with a >50% increase from a previous value known or presumed to have occurred within 7 days	Admission and follow-up lactate	Elevated lactate predicted 1-week mortality	Some methodological concern. AKI was defined using creatinine criteria without urine-output assessment, and external validation was not reported. Lactate may identify short-term mortality risk in ED patients with AKI but should be interpreted as a systemic severity marker.
Wang and Yu, 2025 [66]	MIMIC-IV cohort of critically ill patients with sepsis-associated AKI	Lactate-to-albumin ratio	Higher LAR was associated with higher in-hospital, 30-day, and 90-day mortality	Some methodological concern. LAR is influenced by lactate metabolism, albumin level, inflammation, liver function, nutrition, fluid dilution, and unit definitions. It may support mortality risk stratification in SA-AKI, but thresholds require unit-consistent validation before transfer across studies.
Chen et al., 2025 [60]	Dual-center cohort of adults undergoing on-pump cardiac surgery; postoperative AKI assessed by KDIGO serum-creatinine changes within 7 days	Intraoperative baseline, mean, peak, and time-weighted average lactate	Higher intraoperative lactate burden was associated with postoperative AKI	Some methodological concern. Urine-output data were unavailable, and lactate burden may reflect CPB exposure, procedural complexity, hypotension, transfusion, vasoactive support, or residual confounding. CART-derived thresholds were reported, but discrimination, calibration, and external validation were not reported.
Wang et al., 2025 [61]	Acute type A aortic dissection treated with TAR + FET; severe AKI defined as KDIGO stage 3	Perioperative lactate, especially 12-h postoperative lactate	12-h postoperative lactate showed the strongest signal for severe AKI	Some methodological concern. The cohort was highly selected and surgery-specific, with modest discrimination and no external validation. The 12-h postoperative lactate threshold may help identify severe AKI risk after high-risk aortic surgery but should not be generalized beyond this setting without validation.
Flores-Salinas et al., 2024 [64]	Single-center cross-sectional study of adult cardiac surgery patients; AKI defined by KDIGO 2012 creatinine or urine-output criteria	Postoperative lactate at T0 and T4	T0 and T4 lactate predicted cardiac surgery-associated AKI	Substantial methodological concern. ROC performance was reported, but calibration and external validation were not reported. Single-center design, limited adjustment, and lack of preoperative lactate adjustment limit applicability. Early postoperative lactate may support AKI surveillance but should not replace creatinine, urine-output monitoring, or perioperative risk assessment.
Ekart et al., 2025 [67]	ICU patients with KDIGO stage 3 AKI requiring RRT	Admission lactate; hyperlactatemia > 4 mmol/L	Hyperlactatemia was associated with 60-day mortality	Some methodological concern. This study primarily addressed mortality prediction in severe AKI requiring RRT, not renal recovery. Admission lactate may identify a high-mortality phenotype but should not be used to infer dialysis independence or readiness for RRT discontinuation.
Passos et al., 2016 [68]	Septic AKI patients requiring CRRT	Initial lactate, 24-h lactate, lactate clearance, and lactate kinetics	24-h lactate and lactate clearance were associated with 48-h and 28-day mortality	Some methodological concern. CRRT may alter lactate kinetics through extracorporeal clearance, dilution, acid–base correction, buffer composition, effluent dose, and filter performance. Lactate clearance may support mortality risk assessment but should not be interpreted as spontaneous renal recovery or CRRT adequacy.
Laimoud et al., 2024 [69]	Post-cardiotomy VA-ECMO	12-h/24-h lactate and lactate clearance	Higher lactate levels and lactate kinetics were associated with mortality.	ECMO modifies oxygen delivery and perfusion; lactate should be interpreted as a marker of recovery from circulatory failure rather than extracorporeal clearance.

Abbreviations. AKI: acute kidney injury; CART: classification and regression tree; CPB: cardiopulmonary bypass; CRRT: continuous renal replacement therapy; ICU: intensive care unit; KDIGO: Kidney Disease: Improving Global Outcomes; LAR: lactate-to-albumin ratio; RRT: renal replacement therapy; SA-AKI: sepsis-associated acute kidney injury; TAR + FET: total arch replacement with frozen elephant trunk implantation; TWA: time-weighted average; ECMO: extracorporeal membrane oxygenation; VA-ECMO: veno-arterial extracorporeal membrane oxygenation.

Note. This table provides a study-level critical appraisal of representative clinical evidence on lactate-related indices in AKI-relevant settings. The appraisal was informed by methodological domains commonly considered in PROBAST and QUIPS, including participant selection, predictor measurement, AKI outcome definition, confounding, model performance reporting, validation, and applicability. Because this review is narrative rather than systematic, formal item-by-item risk-of-bias scoring was not performed. Methodological concerns were qualitatively described according to the number and severity of study limitations. “Some methodological concern” indicates important but non-overriding limitations, whereas “substantial methodological concern” indicates coexisting limitations that more clearly restrict interpretability or applicability. Full covariate lists and model diagnostics were not reproduced; when discrimination, calibration, or validation was not reported or could not be confirmed, these elements were not inferred.

Association between lactate levels and AKI severity and short-term outcomes

The clinical significance of lactate in AKI does not end with incident risk. In multiple studies, higher lactate levels have also been associated with greater disease severity, heavier organ support requirements, and worse short-term outcomes [16,21,23,67]. Similarly, Ekart et al. showed that admission hyperlactatemia was independently associated with 60-day mortality among ICU patients with KDIGO stage 3 AKI requiring RRT, supporting its role in mortality risk stratification; however, the study did not evaluate renal recovery or dialysis independence [67]. This pattern is particularly consistent in sepsis-associated AKI, where lactate often rises in parallel with broader circulatory failure, microcirculatory dysfunction, and multisystem stress rather than with kidney injury alone [21,23,70,71].

In practical terms, patients with higher lactate levels tend to present with more severe AKI phenotypes and greater need for intensive support, including vasoactive therapy, mechanical ventilation, and CRRT [66,67,72]. Stratified analyses have shown that patients in higher lactate categories not only have more severe kidney injury but also experience worse short-term survival [16,66,67]. The signal therefore extends beyond AKI occurrence and into the overall severity of illness in which AKI is embedded [16,67]. This is one reason lactate often performs more consistently as a marker of short-term prognostic burden than as a purely renal risk indicator [16,67].

Higher lactate does not directly quantify renal structural damage; rather, it reflects systemic processes that often accompany more severe AKI, including shock, inflammation, impaired perfusion, and altered cellular metabolism [8,10,21,26,67]. In critically ill AKI populations, it is therefore more informative for prognostic enrichment than for renal lesion characterization and cannot replace established renal indices [5–7,21,67].

Clinical value of dynamic assessment using serial lactate changes

If a single lactate measurement provides a static snapshot, serial changes in circulating lactate concentration add directional information [9,73,74]. In this review, the term “lactate clearance” is used according to common clinical usage and refers to the percentage decrease in circulating blood lactate concentration over a defined time interval, commonly calculated as [(initial lactate − repeat lactate)/initial lactate] × 100%. It does not indicate direct measurement of whole-body lactate clearance, hepatic lactate clearance, renal lactate clearance, or extracorporeal lactate removal. Dynamic lactate-related indices may provide useful temporal information in selected high-acuity settings, but they should not be assumed to outperform baseline lactate or conventional clinical assessment unless incremental value has been formally demonstrated for the specific endpoint under study, such as incident AKI, organ-support requirement, or mortality after AKI diagnosis [73–75]. Compared with an isolated lactate value, serial lactate changes may help describe whether physiologic stress is receding, whether perfusion is improving, and whether early treatment is altering the patient’s trajectory over time [73,74].

This dynamic dimension is particularly relevant in sepsis and in patients requiring CRRT [21,68,75–77]. In septic patients without established AKI at baseline, a greater conventionally defined lactate decrease has been associated with a lower risk of incident AKI and more favorable short-term outcomes [75,76,78]. In septic AKI requiring CRRT, Passos et al. reported that 24-h lactate concentration and conventionally defined lactate clearance were associated with 48-h and 28-day mortality [68]. Importantly, these associations support short-term prognostic interpretation rather than direct quantification of extracorporeal lactate removal, spontaneous renal recovery, or CRRT adequacy. Therefore, serial lactate changes should be interpreted according to the endpoint under consideration: incident AKI risk in patients without AKI at baseline, severity or organ-support requirement after AKI develops, or mortality risk among patients with established AKI. These findings suggest that serial lactate assessment may support short-term prognostic interpretation in selected high-acuity settings, especially when the clinical question is whether the patient is improving, remaining unstable, or deteriorating over time [68,73,74,78].

Important limitations should be recognized. Conventionally defined lactate clearance is mathematically coupled to the initial lactate concentration, so apparent associations may partly reflect baseline severity. Repeat measurement windows vary widely, from early reassessment within several hours to 24-h values, and proposed thresholds such as a 10% decrease in lactate concentration have not been consistently externally validated. In addition, lactate kinetics are influenced by hepatic metabolism, adrenergic stimulation, fluid resuscitation, vasopressor exposure, mitochondrial dysfunction, and extracorporeal therapies. A fall in circulating lactate concentration therefore indicates a change in global lactate balance, not necessarily renal recovery.

At the same time, serial lactate changes should not be interpreted mechanically. An early fall in lactate after resuscitation may indicate improving perfusion, but it does not automatically mean that kidney injury has stabilized [9,73,74]. Conversely, persistent hyperlactatemia does not prove ongoing renal hypoperfusion, because later lactate kinetics may also reflect mitochondrial dysfunction, inflammatory activation, impaired hepatic or renal metabolism, or the physiologic effects of organ support [9,68,73,74,76]. The meaning of serial lactate changes therefore shifts with timing, treatment phase, and disease context.

Serial lactate assessment is best viewed as a context-sensitive monitoring approach that adds temporal depth to assessment of the patient’s trajectory when interpreted with hemodynamic variables, renal function trends, and treatment context [9,73,74,78].

Importantly, serial lactate improvement should not be overextended into an AKI-specific therapeutic target or surrogate endpoint. Major sepsis resuscitation trials, including ARISE, ProMISe, and ProCESS, evaluated protocolized early goal-directed resuscitation strategies rather than lactate-guided AKI management per se [79–81]. Their relevance to sepsis-associated AKI is therefore indirect: they caution against assuming that protocol-driven improvement in physiologic targets necessarily translates into improved clinical outcomes in contemporary care. Thus, serial lactate measurements may support reassessment of systemic illness severity and treatment response, but they should not replace conventional kidney assessment.

CRRT and lactate interpretation

Lactate interpretation becomes more complex once continuous renal replacement therapy (CRRT) is initiated. In this setting, measured lactate reflects the interaction between endogenous lactate production, systemic metabolism, treatment-related changes, and extracorporeal removal. Although CRRT can remove lactate from the circulation, direct extracorporeal lactate removal at conventional CRRT doses is usually limited relative to the high rate of endogenous lactate production seen in severe shock or sepsis [82–84]. The quantitative contribution of extracorporeal lactate removal appears limited compared with whole-body lactate turnover. In a prospective physiologic study of critically ill patients receiving continuous venovenous hemofiltration with dialysis, Levraut et al. estimated a median total plasma lactate clearance of 1379 mL/min, whereas median filter lactate clearance was only 24.2 mL/min, accounting for less than 3% of total lactate clearance. These findings indicate that, although lactate is readily diffusible across CRRT membranes, conventional CRRT doses generally cannot offset substantial endogenous lactate overproduction during severe shock or sepsis [85]. Therefore, an improvement in circulating lactate during CRRT should not be attributed primarily to extracorporeal clearance unless the treatment dose, lactate load, buffer composition, and broader clinical trajectory support such an interpretation.

CRRT may influence serial lactate values through several distinct mechanisms. First, lactate may be removed directly across the extracorporeal circuit, although this contribution is commonly modest in relation to ongoing systemic production. Second, measured concentrations may change because of dilution, fluid administration, ultrafiltration, and shifts in the volume of distribution. Third, correction of acidemia may improve cellular metabolism and hemodynamic responsiveness without necessarily indicating improved intrinsic renal lactate handling. Fourth, changes in systemic perfusion after resuscitation, vasopressor adjustment, fluid removal, or source control may reduce endogenous lactate generation. Finally, when lactate-buffered dialysate or replacement fluid is used, exogenous lactate delivery may contribute to circulating lactate levels and complicate interpretation [84].

Clinical studies reinforce the distinction between prognostic lactate kinetics and extracorporeal lactate clearance. In 186 patients with septic AKI requiring CRRT, Passos et al. found that 24-h lactate and conventionally defined lactate clearance, but not initial lactate, were independently associated with mortality, with 24-h lactate showing the best discrimination for 28-day mortality [68]. In a MIMIC-III cohort of 717 patients with SA-AKI, Wang et al. reported that longitudinal lactate trajectories were associated with 28-day mortality, whereas CRRT use itself was not independently associated with survival [77]. In 1,661 patients receiving CRRT for severe AKI, Kim et al. found a graded association between lactate at CRRT initiation and in-hospital mortality, and lactate improved discrimination when added to SOFA- and APACHE II-based models [86]. Together, these findings support lactate as a marker of short-term prognostic trajectory during CRRT rather than as a surrogate for CRRT efficacy, extracorporeal clearance, or renal recovery [68,77,86]. More recently, studies focusing on lactate kinetics during CRRT have emphasized that temporal lactate patterns represent the interaction between systemic lactate production, metabolic recovery, and extracorporeal support rather than extracorporeal clearance alone. Therefore, lactate trajectories during CRRT should be interpreted within the broader context of treatment response and illness evolution.

From a bedside perspective, lactate dynamics during CRRT should not be interpreted in the same way as spontaneous lactate decline in patients not receiving RRT. Persistent hyperlactatemia during CRRT may indicate ongoing shock, sepsis, hepatic dysfunction, mitochondrial stress, inadequate source control, or insufficient reversal of systemic metabolic stress, but it does not by itself prove persistent renal hypoperfusion. Similarly, a decline in lactate after CRRT initiation more often reflects a changing balance among systemic lactate production, tissue perfusion, hepatic metabolism, acid–base status, resuscitation, and extracorporeal effects rather than recovery of intrinsic kidney function. Clinically, lactate trends during CRRT should be interpreted together with CRRT modality, effluent dose, buffer composition, filter function, fluid balance, vasopressor requirement, liver function, infection control, and the timing of measurement relative to CRRT initiation [82,83,86]. In this setting, lactate trends are more appropriate for short-term prognostic reassessment than for judging AKI recovery or intrinsic renal metabolic recovery.

ECMO and combined ECMO–CRRT support

ECMO adds a distinct interpretive context because lactate may change rapidly after cannulation as circulatory or respiratory support modifies systemic oxygen delivery and perfusion [69,87]. In 152 adults receiving postcardiotomy VA-ECMO, Laimoud et al. found that lactate levels at 12 and 24 h and conventionally defined lactate clearance were associated with in-hospital mortality; however, absolute lactate values at matched time points discriminated mortality better than clearance percentages [69]. In a 2026 multicenter cohort of 1,484 patients with severe pneumonia receiving VV-ECMO, Li et al. identified the 24-h lactate concentration as the most important variable associated with in-hospital mortality in a machine-learning analysis of 341 candidate variables [88]. These findings support the prognostic relevance of serial lactate assessment during ECMO but also caution against transferring a single lactate threshold or clearance target across VA-ECMO and VV-ECMO populations [69,88].

Interpretation becomes still more complex when CRRT is combined with ECMO. The 2026 ADQI–ELSO consensus noted that approximately half of patients receiving ECMO undergo renal replacement therapy and emphasized important evidence gaps, including the lack of randomized evidence defining optimal CRRT timing during ECMO [87]. In the RESCUE registry, lactate remained a consistent independent predictor of both 72-h and 30-day mortality regardless of ECMO or CRRT utilization, while the association between CRRT and mortality differed according to the time horizon examined [89]. A 2026 multicenter study published in Renal Failure found higher in-hospital mortality among ECMO patients receiving CRRT, particularly in the VA-ECMO subgroup; however, its retrospective observational design does not establish that CRRT itself caused the excess risk [90]. Accordingly, during ECMO with or without CRRT, lactate is best interpreted as an integrated marker of evolving systemic perfusion, metabolic stress, disease severity, and organ-support context rather than as a direct measure of extracorporeal lactate removal, CRRT adequacy, or intrinsic renal recovery [87,89,90].

Evidence gaps, negative findings, and risk of overinterpretation

Several limitations prevent lactate-related indices from being used as AKI-specific decision tools. First, most available clinical studies are observational, and many are retrospective or single-center, making residual confounding and indication bias difficult to exclude. Second, lactate sampling windows, thresholds, and dynamic calculations vary substantially across studies, which limits comparability and weakens the transferability of proposed cutoffs. Third, many studies report statistical associations without demonstrating incremental value beyond illness severity scores, hemodynamic variables, serum creatinine, urine output, vasopressor exposure, hepatic dysfunction, or established kidney injury biomarkers. Fourth, external validation, calibration, reclassification analysis, and decision-curve analysis are often absent [22,24,91,92].

These limitations are consistent with broader concerns about biomarker-based prediction and prognostication in AKI-relevant settings, including recent evidence that neither routine nor novel biomarkers showed sufficient accuracy for predicting RRT-initiation criteria in severe AKI [22,24,25,93]. Chaïbi and colleagues emphasized that many proposed biomarkers or prediction tools remain attractive in concept but difficult to translate into reliable decisions about AKI development or renal replacement therapy initiation [22,93]. This caution is directly relevant to lactate-related indices: a statistically significant association between lactate and an AKI-related endpoint, whether incident AKI, RRT requirement, or mortality after AKI diagnosis, does not necessarily mean that lactate improves clinical decision-making, identifies structural kidney injury, or provides an actionable treatment threshold.

Cautionary evidence comes from several levels: biomarker-prediction critiques in AKI, methodological pitfalls in interpreting conventionally defined lactate clearance, and large sepsis resuscitation trials evaluating protocolized early goal-directed approaches [9,22,73,79–81]. The pitfalls described by Hernandez and colleagues and by Levy and colleagues support interpreting conventionally defined lactate clearance as a global physiologic signal rather than an AKI-specific surrogate. ARISE, ProMISe, and ProCESS should be interpreted more narrowly. These trials were not designed to test lactate-guided AKI management, nor do they demonstrate that serial lactate monitoring is clinically useless. Rather, they provide indirect caution that protocolized pursuit of physiological targets does not necessarily improve patient-centered outcomes compared with contemporary usual care. These findings reinforce the need to treat lactate-related indices as adjunctive information for endpoint-specific risk assessment and clinical reassessment, rather than as stand-alone markers of renal injury, renal recovery, RRT requirement, or AKI-specific treatment response.

Limitations of lactate as a clinical marker in AKI assessment

The clinical usefulness of lactate in AKI is real, but so are its limitations [8,10,13,21,26]. The central problem is not lack of signal but lack of specificity [8,10,13]. Lactate is shaped by production, transport, utilization, and clearance across multiple organs and physiologic systems, and any increase reflects the combined effect of these processes rather than a discrete renal event or a direct measure of renal parenchymal injury [8,10,11,13,26].

In clinical practice, hyperlactatemia may result from sepsis, shock, hepatic dysfunction, catecholamine exposure, seizures, trauma, intoxication, impaired metabolic clearance, extracorporeal therapies, or combinations of these factors [8,10,26]. Kidney dysfunction may contribute, but it is rarely the sole determinant [11,13]. Even within AKI populations, the meaning of lactate varies with disease stage, hemodynamic status, resuscitation intensity, liver function, organ support, and the relative balance between systemic and renal mechanisms [9,21,73,74]. Treating lactate as a direct readout of kidney injury, renal hypoperfusion, or renal recovery therefore overstates what the marker can deliver [12,13,21].

For these reasons, lactate is best used within a broader framework that includes renal indices, hemodynamic status, liver function, treatment exposure, renal replacement therapy status, illness severity, and, when available, kidney injury biomarkers [5–7,21,56]. In that role, it can enrich clinical reassessment; in isolation, it should not be used to diagnose AKI, quantify structural injury, infer renal recovery, or guide AKI-specific treatment decisions [21,22,56,57].

Applications of lactate-related indices in different clinical settings of AKI

Across clinical settings, the practical issue is where lactate is most informative, what it primarily reflects, and where extrapolation becomes less reliable [21,22,56,57].

Sepsis-Associated AKI in the intensive care unit

Sepsis-associated AKI is the setting in which lactate-related indices have been studied most extensively and, at present, the setting in which their clinical relevance appears strongest [21,23,71]. In septic ICU patients, hyperlactatemia often develops alongside circulatory failure, microcirculatory dysfunction, inflammatory activation, and metabolic stress, all of which are closely linked to the development and progression of AKI [21,23,41–44,70,71]. In this context, lactate reflects the broader physiologic environment in which kidney injury emerges and worsens rather than kidney injury in isolation [16,21,23,70,71].

Elevated lactate in septic patients has been associated with several distinct AKI-relevant outcomes, including a higher risk of incident SA-AKI, greater disease severity after AKI develops, increased need for organ support, and poorer short-term survival among patients with SA-AKI [16,63,66,75]. Dynamic lactate-related indices, such as serial lactate changes or conventionally defined lactate clearance, may be particularly useful because they provide information not only about baseline risk but also about the direction of illness over time [68,75,76,77,78]. Lactate-related composite indices, including the lactate-to-albumin ratio, may further improve endpoint-specific risk stratification, such as incident SA-AKI risk or mortality risk among patients with established SA-AKI, although current evidence remains concentrated in selected ICU cohorts [63,66].

In septic AKI, the main limitation is interpretive rather than associative: even in sepsis, lactate cannot by itself distinguish renal from non-renal contributors to physiologic deterioration [8,10,21,26]. Its role is therefore to support risk recognition and reassessment within the broader physiologic context, rather than to diagnose kidney injury [21,23,56].

Perioperative AKI and cardiac surgery-associated AKI

Outside sepsis, the perioperative setting—especially cardiac and major vascular surgery—is the second major context in which lactate-related indices have shown clinically relevant value [94,95]. Here, the dominant drivers are not infection and systemic inflammatory dysregulation alone, but a shifting combination of intraoperative hypoperfusion, ischemia-reperfusion injury, cardiopulmonary bypass exposure, surgical stress, oxygen supply-demand imbalance, and early postoperative hemodynamic instability [94–99].

In this setting, lactate appears most useful as a time-sensitive warning signal [60,61,64,94,95]. Studies have shown that intraoperative lactate burden, whether assessed by baseline, mean, peak, or time-weighted average values, is associated with postoperative AKI after cardiac surgery [60,61,64]. Chen et al. further reported that intraoperative lactate burden, including baseline, mean, peak, and time-weighted average lactate, was associated with postoperative AKI after on-pump cardiac surgery, although interpretation remained limited by possible procedure-related confounding and lack of external validation [60]. Early postoperative measurements may also be informative, particularly when they capture sustained rather than transient perioperative stress [64,100].

This time dependence has two implications. First, perioperative lactate may help identify patients at heightened risk before overt renal dysfunction becomes apparent [60,61,64,94,95]. Second, thresholds derived from one surgical context should not be transferred casually to another [94,95,100]. A lactate value that carries meaningful risk information after cardiac bypass may not have the same meaning after non-cardiac surgery, and even within cardiac surgery its interpretation varies with procedural complexity, bypass duration, transfusion burden, and postoperative resuscitation intensity [94–100].

Accordingly, the clinical value of lactate-related indices in perioperative AKI lies mainly in early warning and perioperative risk enrichment, particularly in cardiac and major vascular surgery, rather than in broad prognostic transfer across surgical populations [60,61,64,94,98,100]. The signal is clinically useful, but narrower and more context-bound than in ICU sepsis [21,94,95].

Emergency department and general ward settings

Evidence outside the ICU is limited but not absent. Bayar et al. reported that admission and follow-up lactate measurements predicted 1-week mortality among emergency department patients with AKI [65]. However, AKI was defined using creatinine criteria without urine-output assessment, and external validation was not reported. This study therefore supports lactate as a supplementary short-term systemic severity marker in selected ED patients rather than as a validated AKI-specific threshold.

Outside the ICU, patients are more heterogeneous, severe circulatory dysfunction is less uniform, and the pretest probability of intense systemic stress is often lower or more variable [101–103]. Under these conditions, lactate may still mark higher overall risk, but its relationship to AKI becomes less direct and less consistent. A marker that performs reasonably well in septic shock or in patients treated with continuous renal replacement therapy cannot simply be assumed to retain the same meaning in emergency triage or general inpatient care [21,101–103].

Outside the ICU, lactate may contribute to general risk assessment in selected unstable patients, but the evidence does not yet support standardized AKI-focused use, reliable thresholds, or proven incremental value over conventional assessment [22,56,57,101–103]. In emergency department and general ward settings, it is therefore better viewed as a supplementary severity signal than as a validated AKI-focused tool [102].

Research priorities for clinical translation

The next phase of research should move beyond repeatedly showing that higher lactate is associated with worse outcomes [21,22,93]. That association is already well established, particularly in sepsis-associated AKI and selected critical care cohorts [21,23,70,71]. The remaining task is to determine where lactate-related indices add stable clinical value, how well that value holds across settings, and whether these indices can meaningfully support bedside decisions [22,56,57,91,92].

Several priorities follow. First, future studies need better standardization of timing [22,56,57,91,92]. Baseline lactate, peak lactate, 24-h lactate, conventionally defined lactate clearance, and trajectory-based models are often discussed together even though they may address different clinical questions, including incident AKI risk, organ-support requirement, or mortality risk among patients with established AKI [68,73–78]. Comparability will remain limited until timing windows are matched more explicitly to intended use [22,56,57,91,92]. Second, dynamic lactate-related indices and lactate-related composite indices should be tested directly against baseline lactate and conventional renal markers rather than merely reported as statistically significant. The relevant question is not whether a new lactate-related index reaches statistical significance, but whether it improves discrimination, calibration, reclassification, or practical bedside usefulness in a clinically meaningful way [24,25,91,92]. Third, broader validation is necessary. Current evidence remains heavily concentrated in ICU sepsis, CRRT populations, and cardiac surgery. Emergency department and general ward cohorts, as well as more diverse AKI phenotypes, remain underrepresented [56,91,92,101–103]. Fourth, future work should focus more explicitly on integration [22,56,57]. The most promising role for lactate-related indices is unlikely to be as isolated markers, but as components of multidimensional assessment strategies that incorporate serum creatinine, urine output, hemodynamic variables, and kidney injury biomarkers [5–7,22,56,57].

Ultimately, the goal is not to show once again that lactate matters, but to define more precisely when it matters, for whom it matters, and what clinical decisions its measurement can meaningfully support [22,56,57,91,92].

Bedside interpretation of lactate in AKI

For bedside use, lactate in AKI should not be interpreted by asking whether it is “renal” or “nonrenal” in origin. In most clinical situations, such a distinction is not possible from the lactate value itself. A more useful approach is to determine what clinical question the lactate measurement is being used to answer. If the question is whether AKI is present or whether renal structural injury has occurred, lactate is not an appropriate diagnostic marker. When lactate is used for prognostic interpretation, it should be linked to a defined endpoint rather than described broadly as AKI prediction [10,104,105].

Once the clinical endpoint is defined, lactate should be interpreted differently according to the question being asked. For incident AKI risk, early lactate elevation or an unfavorable early lactate trajectory may support risk enrichment in selected high-acuity settings, but lactate should not be used to diagnose AKI [60–62,64]. For illness-severity assessment after AKI is established, higher or persistent lactate should be interpreted primarily as a marker of greater systemic physiologic burden and considered together with hemodynamics, vasopressor requirement, organ-support intensity, and established severity scores rather than as a kidney-specific measure of injury severity [67,72,85]. For short-term prognosis, 24-h lactate and serial lactate trajectories may provide temporal prognostic information in selected ICU and CRRT populations; persistent elevation or failure to decline is generally associated with worse short-term outcomes [62,68,77,85]. Conversely, a fall in circulating lactate indicates an improvement in global lactate balance and should not be equated with renal recovery [9,68,73,74].

The next step is to interpret the selected endpoint within the relevant clinical setting. In septic shock or sepsis-associated AKI, elevated lactate is most plausibly interpreted as a marker of combined circulatory, inflammatory, and metabolic stress rather than as a renal signal in isolation. In perioperative AKI, especially after cardiac or major vascular surgery, lactate is better viewed as a time-sensitive indicator of intraoperative and early postoperative physiological burden. In patients receiving CRRT, and especially in those supported with ECMO with or without CRRT, lactate trends require additional caution because measured concentrations reflect changing systemic perfusion and metabolism together with fluid balance, acid–base correction, circuit-related effects, and other treatment exposures. Serial lactate in this setting is therefore more appropriate for trajectory-based prognostic reassessment than for inferring renal recovery, CRRT adequacy, or the magnitude of extracorporeal lactate removal [86–90]. In emergency department or general ward patients, current evidence is insufficient to support standardized AKI-specific lactate thresholds.

The second step is to consider timing. Early lactate elevation may support risk enrichment when AKI has not yet fully declared itself. Persistent hyperlactatemia after initial resuscitation should prompt reassessment of shock, sepsis control, hepatic function, mitochondrial dysfunction, treatment exposure, and adequacy of organ support, but it should not be assumed to indicate ongoing renal hypoperfusion. Conversely, a decline in circulating lactate concentration may suggest improvement in global lactate balance, but it does not prove renal recovery or stabilization of tubular injury.

Therefore, the bedside value of lactate in AKI lies in framing clinical risk and prompting reassessment, not in defining kidney injury. It can help identify patients who require closer monitoring, reassessment of perfusion or sepsis control, or more integrated evaluation of organ dysfunction. Box 1 provides an endpoint-oriented framework for bedside interpretation of lactate in AKI, outlining where lactate may provide clinically relevant information and where its use remains unsupported.

Box 1.

Practical bedside interpretation of lactate in AKI-relevant settings.

Clinical setting	Lactate can support	Lactate should not be used to
Sepsis-associated AKI / septic shock	Prompt reassessment of circulatory stress, sepsis control, organ support needs, dynamic illness trajectory, and short-term prognostic risk when interpreted together with hemodynamics, vasopressor exposure, serum creatinine, and urine output.	Diagnose AKI, distinguish renal from non-renal causes of deterioration, infer structural kidney injury, or treat lactate clearance as an AKI-specific therapeutic target.
Perioperative AKI / cardiac or major vascular surgery	Identify sustained intraoperative or early postoperative physiologic stress and support closer AKI surveillance, especially after cardiac or high-risk vascular surgery.	Transfer thresholds across surgical procedures, replace creatinine or urine-output monitoring, or interpret transient postoperative lactate elevation as direct evidence of kidney injury.
AKI requiring CRRT/RRT or ECMO-supported organ support	Monitor global metabolic trajectory and short-term risk together with extracorporeal support modality, CRRT parameters (when applicable), fluid balance, systemic perfusion, vasopressor requirement, liver function, and infection control.	Interpret lactate clearance as spontaneous renal recovery, CRRT adequacy, dialysis independence, or readiness for RRT discontinuation.
Emergency department or general ward settings	Provide a supplementary signal of systemic stress and overall short-term risk in selected unstable patients or patients with established AKI.	Apply ICU-derived or sepsis-derived AKI thresholds, use lactate for standardized AKI-specific risk stratification, or replace conventional AKI assessment.

This box summarizes setting-specific clinical interpretability, major limitations, and bedside readiness discussed in the corresponding sections above.

Abbreviations: AKI: acute kidney injury; CRRT: continuous renal replacement therapy; ECMO: extracorporeal membrane oxygenation; ICU: intensive care unit; RRT: renal replacement therapy.

Conclusion

Current evidence supports a clinically useful but clearly bounded role for lactate-related indices in AKI, particularly in sepsis-associated AKI, critical illness requiring organ support, and selected perioperative populations [8,13,21,60,67].

Elevated lactate, persistent hyperlactatemia, or failure of circulating lactate concentration to decline may warrant reassessment of perfusion, sepsis control, hepatic function, vasopressor exposure, extracorporeal therapies, and the broader illness trajectory. Dynamic lactate-related indices may add temporal information, but they should not be interpreted as direct evidence of renal recovery, persistent renal hypoperfusion, structural kidney injury, or AKI-specific treatment response [9,68,73,77]. Thus, the clinical meaning of lactate in AKI depends primarily on the physiological and clinical context in which it is measured rather than on lactate concentration alone.

The main challenge is to determine when lactate-related indices add clinically meaningful information beyond conventional AKI assessment. Future studies should focus on defining when lactate-related indices provide incremental clinical value beyond established assessment strategies, including conventional renal parameters, severity scores, and organ-support indicators, rather than relying solely on statistical associations [22,24,91,92].

Funding Statement

The author(s) reported there is no funding associated with the work featured in this article.

Ethical approval

Ethical approval was not required because this article is a review of published literature.

Disclosure statement

The authors have no conflicts of interest to declare.

Data availability statement

No new data were created or analyzed in this study. Data sharing is not applicable to this article.