Hyperlactatemia in sepsis and shock: a renal metabolic perspective

Abstract

Hyperlactatemia is a frequent finding in critically ill patients and is traditionally interpreted as a marker of tissue hypoxia and anaerobic metabolism. However, in sepsis, septic shock, and other states of circulatory failure — including post-cardiac arrest syndrome — elevated lactate concentrations often occur despite preserved arterial oxygenation and adequate oxygen delivery. Increasing evidence indicates that lactate is a central metabolic intermediate whose circulating concentration reflects the balance between stress-induced production, cellular utilization, and organ clearance. While hepatic metabolism has long been considered the dominant pathway for lactate disposal, the kidneys — particularly proximal tubular cells — play a major and often underappreciated role in lactate utilization and clearance. Acute kidney injury (AKI), a common complication of sepsis, directly alters systemic lactate homeostasis. In this narrative review, we synthesize current knowledge on lactate biology in critical illness and examine the contribution of renal metabolism to hyperlactatemia in patients with sepsis-induced AKI. We propose that lactate should be interpreted as an integrated metabolic signal reflecting systemic stress and impaired clearance — rather than as a surrogate for hypoxia alone — with important implications for the management of septic AKI. The potential of urinary lactate as a marker of proximal tubular metabolic dysfunction and the emerging role of protein lactylation in modulating the inflammatory-to-reparative phenotypic transition are also discussed.

Introduction

The measurement of blood lactate concentration is deeply embedded in the management of critically ill patients. Elevated lactate levels are commonly interpreted as indicators of tissue hypoxia, oxygen debt, and disease severity, and lactate-guided resuscitation strategies are widely applied in the management of sepsis and septic shock [1, 2]. Despite its widespread clinical use, the interpretation of hyperlactatemia remains controversial.

Hyperlactatemia occurs across a broad spectrum of critical illness — including sepsis, post-cardiac arrest syndrome, cardiogenic shock, hemorrhagic shock, and distributive shock of other causes — reflecting shared final pathways of altered lactate production and clearance (Fig. 1). The focus of this review is septic AKI, but the renal metabolic mechanisms discussed apply broadly to states of sustained circulatory failure. In all these contexts, hyperlactatemia frequently develops despite preserved arterial oxygenation and restoration of macrocirculatory targets [3, 4]. Importantly, this observation does not in itself challenge the classical view: even after macrocirculatory restoration, microcirculatory heterogeneity may persist, producing localized tissue hypoxia despite normalized global hemodynamic variables. Experimental studies support this complexity. In a tamponade model, full restoration of both global and microcirculatory perfusion did not completely normalize lactate levels [5], underscoring the difficulty of interpreting lactate kinetics even when hemodynamic endpoints are met.

Fig. 1.

Sepsis- or shock-associated AKI affects both lactate production and clearance, leading to hyperlactatemia. Circulating lactate reflects the balance between stress-induced production and organ clearance. The liver and kidneys are the major organs responsible for lactate clearance. In the kidney, proximal tubular cells rely on mitochondrial oxidative metabolism to utilize lactate. AKI may impair intracellular lactate recycling, leading to the early secretion of lactate into urine. Lactaturia interpretation might be difficult in presence of lactate “spillover” when plasma lactate level overwhelmed the tubular reabsorption capacity

Lactate can indeed arise both from impaired oxygen delivery — reflected by an elevated lactate-to-pyruvate ratio and VO2/DO2 mismatch — and from oxygen-independent mechanisms including adrenergic or cytokine-driven aerobic glycolysis, immune cell activation, and impaired organ clearance. Tissue hypoxia, particularly during the hyperacute phase of septic shock, is likely a dominant mechanism and should be addressed urgently. As resuscitation proceeds and macrocirculatory targets are restored, the relative contribution of clearance-limited and metabolic mechanisms increases. It is worth noting that moderate to severe hyperlactatemia (> 4–5 mmol/L), as may occur in severe septic shock or diffuse malignancy, likely reflects non-hypoxic mechanisms that cannot be attributed to only hypoxia-driven generation. However, lactate levels alone are unlikely to indicate the underlying mechanism of hyperlactatemia. Experimental and clinical studies have indicated that lactate is not merely a waste product of glycolysis but a central metabolic intermediate involved in energy transfer, redox balance, and inter-organ communication [6, 7].

Circulating lactate concentration reflects the net balance between production, utilization, and clearance (Fig. 1). Increased production may arise from adrenergic stimulation [8], immune cell activation and accelerated aerobic glycolysis [9], whereas impaired utilization and clearance contribute to sustained hyperlactatemia. Although the liver has traditionally been regarded as the principal organ for lactate clearance, the kidneys play a substantial and underestimated role [10, 11], contributing up to 40% of gluconeogenesis under physiological conditions [12]. Because of this, septic AKI can shift hyperlactatemia from a production-dominant to a clearance-limited phenotype [10–13]. Importantly, continued resuscitation aimed solely at normalizing lactate may be associated with harm in stabilized patients [14], reinforcing the importance of contextual interpretation over reflexive lactate-chasing. Reframing lactate as an inter-organ metabolic flux substrate—rather than a single-point concentration—may improve interpretation of persistent hyperlactatemia after hemodynamic optimization and refine risk stratification in septic shock [1, 2, 11, 13].

Septic AKI is increasingly recognized as a heterogeneous syndrome in which functional and metabolic alterations may predominate over structural injury [11]. Mitochondrial dysfunction, microcirculatory disturbances, and inflammatory signaling impair tubular energetics — particularly in proximal tubular cells with high ATP demand [10, 15] — reducing renal lactate utilization and contributing to persistent hyperlactatemia (Fig. 1).

Lactate biology and determinants of hyperlactatemia in critical illness

Lactate is produced from pyruvate via a reversible reaction catalyzed by lactate dehydrogenase (LDH). This reaction is near equilibrium in most tissues, and its direction depends primarily on the cytosolic redox state — reflected by the NADH/NAD+ ratio — and the rate of pyruvate utilization by the mitochondria [16]. Under physiological conditions, lactate serves as a mobile energy source through inter-organ shuttles: lactate produced in glycolytic tissues is transported to oxidative tissues including the heart, brain, and kidney, where it is converted back to pyruvate and oxidized in the tricarboxylic acid (TCA) cycle [16, 17]. The Cori cycle between muscle and liver is the canonical example. Lactate is therefore a central metabolic intermediate — an oxidative substrate, a gluconeogenic precursor, and a signaling molecule — not merely a metabolic waste product [18]. The net balance between lactate production and clearance are both profoundly altered during sepsis and other forms of critical illness.

Increased lactate production

Multiple non-mutually exclusive mechanisms drive increased lactate production in critical illness. Systemic adrenergic activation accelerates glycolytic flux and promotes lactate production even in the presence of normal oxygen tension, by stimulating Na+/K+-ATPase activity and increasing pyruvate generation beyond mitochondrial oxidative capacity [8]. This ‘aerobic glycolysis’ represents an adaptive stress response that becomes maladaptive when excessive or prolonged, generating lactate to regenerate NAD + and sustain glycolytic flux. This phenomenon, often referred to as stress-induced aerobic glycolysis, has been well described in patients with sepsis and shock [8, 16].

Immune cell activation constitutes an additional source. Activated leukocytes rely heavily on glycolysis for rapid ATP generation and biosynthetic precursor production, releasing lactate as a metabolic byproduct [9, 19, 20]. This immune-driven lactate production reflects inflammation rather than hypoperfusion. Finally, mitochondrial dysfunction, sometimes described as cytopathic hypoxia, may limit the capacity of cells to oxidize pyruvate despite adequate oxygen tension [9, 17, 21].

Regional microcirculatory dysfunction sustains localized tissue hypoxia despite preserved global oxygen delivery. Sepsis-induced endothelial dysfunction and heterogeneity of microvascular flow produce VO2/DO2 mismatch in vulnerable territories — particularly the kidney [22, 23] — generating genuinely hypoxia-driven lactate with an elevated lactate-to-pyruvate ratio.

Impaired lactate clearance

While increased production is important, impaired clearance is a major and clinically underappreciated determinant of hyperlactatemia, particularly after initial resuscitation. The liver and kidneys are the principal organs responsible for lactate removal (Fig. 1). Hepatic dysfunction and hypoperfusion are well-recognized contributors to lactate accumulation in sepsis [24]. The kidney clears lactate through oxidation for energy production and conversion to glucose via gluconeogenesis [1, 24]. These processes predominantly occur in the renal cortex and require intact mitochondrial function. Reduced renal perfusion, tubular dysfunction, and loss of functional nephron mass in AKI impair renal lactate clearance [2, 14].

The term ‘lactate clearance’ as used clinically — referring to the decline in blood lactate concentration over time — does not necessarily reflect true metabolic disposal. Plasma lactate changes represent the net result of shifts in production, distribution, and utilization. True clearance refers specifically to oxidation and gluconeogenesis. This distinction is critical in septic AKI, where reduced renal metabolic function may contribute to persistent hyperlactatemia despite adequate resuscitation, and where lactate may be an unreliable endpoint for titrating further resuscitative efforts.

Renal lactate handling and proximal tubular metabolism

The kidneys play a central role in systemic lactate homeostasis. Circulating lactate is freely filtered at the glomerulus. Under physiological conditions, almost all filtered lactate is reabsorbed in the proximal tubule via monocarboxylate transporters (MCT1/MCT2, and MCT4 on the basolateral side) [25], such that urinary lactate excretion is normally minimal [25, 26]. Renal contributions to systemic lactate balance therefore primarily reflect renal uptake and metabolic processing — oxidation and gluconeogenesis — rather than urinary elimination.

Proximal tubular cells are highly specialized for oxidative metabolism. They contain a dense mitochondrial network and rely predominantly on aerobic ATP production to support energy-intensive processes such as sodium reabsorption and solute transport [27, 28]. Their glycolytic capacity is limited, rendering them particularly vulnerable to disruptions in oxidative metabolism. Once inside proximal tubular cells, reabsorbed lactate is either oxidized through the TCA cycle to generate ATP or used as a gluconeogenic substrate.

In contrast, cells of the renal medulla operate in a physiologically hypoxic environment and exhibit predominantly glycolytic metabolism, generating lactate as a byproduct. This medullary lactate may be released and taken up by cortical proximal tubular cells for oxidation or gluconeogenesis [15, 29]. This intrarenal metabolic compartmentalization — medullary glycolysis fueling cortical oxidative metabolism — mirrors the classic Cori cycle and creates a physiological cortical-medullary lactate gradient [30]. While direct experimental proof in humans remains limited and largely inferential, the spatial metabolic heterogeneity between cortex and medulla is well established at the cellular level.

AKI disrupts these processes. In sepsis, AKI frequently occurs in the absence of overt ischemia, suggesting that functional and metabolic alterations predominate. Mitochondrial dysfunction and inflammatory signaling impair oxidative phosphorylation, reducing the capacity of proximal tubular cells to utilize lactate for energy production [11]. Consequently, renal lactate clearance declines, contributing directly to systemic hyperlactatemia (Fig. 2).

Fig. 2.

Schematic representation of glucose/lactate pathways in proximal tubular cells. Glucose entry via the transporter (GLUT 1,2) into plasma cells is processed to produce pyruvate via glycolysis. Pyruvate has two main fates: first, it is transformed into acetyl-CoA to fuel the tricarboxylic acid (TCA) cycle; second, it is reduced to lactate. Lactate acts then as; first, as an energetic substrate oxidized to pyruvate, subsequently fueling the renal neoglucogenesis; second, extrusion from the proximal cell to blood via monocarboxylic transporter (MCT); third, similarly secreted into the PTC urinary pole creating a lactate in urine; fourth, lactate acts as an immunomodulator via epigenetic lactylation. Cellular plasma glucose levels are also regulated by sodium-glucose cotransporter 2 (SGLT2), a potentially important therapeutic target. Finally, the intensity of glycolysis and glucose levels activate the mammalian target of rapamycin complex 1 (mTORC1)-hypoxia inducible factor 1 alpha (HIF-1α) signaling (mTOR) pathway, which in turn increases the expression of major glycolytic enzymes and stimulates the inflammatory response [9]. In AKI, all these pathways might be shifted to increase glycolysis, lactate production, and potentially release of lactate in urine. Inflammation and oxidative stress induce the activation of complex-1 mTORC1-Hypoxia inducible factor 1 alpha (HIF-1α) signaling. mTORC-1-HIF-1α signaling induces the expression of pyruvate kinase M2 isoform (M1 is the constitutively expressed physiologic enzyme) and pyruvate dehydrogenase kinase (PDHK), both of which are key to triggering aerobic glycolysis, also known as Warburg metabolism. Overproduction of pyruvate overwhelms the capacity of the oxidative phosphorylation mitochondrial machinery, resulting in increased cytosolic concentrations of pyruvate. Pyruvate is thus converted to lactate by the action of lactate dehydrogenase, which is a necessary step for the reconstitution of nicotinamide dinucleotide (NAD⁺) within the cell. Hence, the switch in metabolism toward aerobic glycolysis increases lactate production in normoxia. The induction of aerobic glycolysis, activation of mTORC1-HIF-1α signaling, and hyperlactatemia all contribute to the modification of the phenotype of renal tubular epithelial cells by first altering ion transport functions, leading to oliguria and AKI, and second, by inducing inflammation potentially associated with lactate in urine. Glomerular filtration in the presence of elevated plasma lactate levels may overwhelm tubular reabsorption capacity, leading to lactaturia from a potential spillover from systemic hyperlactatemia. The combination of these factors with lactate reabsorption failure necessitates the measurement of associated markers of tubular dysfunction to separate the mechanisms of lactaturia

Septic AKI as a metabolically heterogeneous syndrome

Septic AKI encompasses distinct pathophysiological phenotypes, each with different implications for lactate metabolism [11, 31, 32]. These include: (i) ischemic AKI driven by reduced renal perfusion; (ii) microcirculatory dysfunction with heterogeneous cortical and medullary flow; (iii) mitochondrial dysfunction with metabolic downregulation; and (iv) venous congestion [32]. These phenotypes are not mutually exclusive and may coexist in the same patient. Several represent adaptive tubular responses that prioritize cell survival over metabolic function.

The distinction between mitochondria-capable and mitochondrially-impaired phenotypes has direct implications for renal lactate handling. In mitochondria-capable phenotypes, proximal tubular cells retain the ability to oxidize lactate and contribute to systemic clearance. In contrast, in phenotypes dominated by mitochondrial dysfunction, lactate utilization is impaired and renal clearance markedly reduced — shifting hyperlactatemia from a production-dominant to a clearance-limited signal. This important distinction cannot be made from plasma lactate concentration alone and helps explain the variable and sometimes paradoxical relationships between lactate levels, renal function, and outcomes in sepsis.

Emerging literature underscores that metabolic reprogramming is central to AKI pathophysiology. Reduced fatty acid oxidation, enhanced glycolysis, redox imbalance, and mitochondrial fragmentation contribute to tubular injury and impaired organ function [10, 11]. In this context, lactate represents both a potentially available metabolic substrate for energetic recovery and a marker of the systemic metabolic state.

Protein and histone lactylation: a novel dimension of lactate signaling

Beyond its role as a metabolic substrate, lactate exerts direct signaling effects through post-translational modifications. Lactylation — the covalent addition of a lactyl group to lysine residues on histones and non-histone proteins — was first characterized in macrophages, where L-lactate was shown to lactylate histone H3 and H4 residues, promoting transcriptional changes [33]. This modification is generated from lactyl-CoA, produced by the enzymatic coupling of lactate and coenzyme A, in reactions facilitated by glycolytic enzymes and acetyltransferases under conditions of elevated intracellular lactate.

In the context of sepsis and AKI, lactylation functions as a biological switch modulating the transition between inflammatory and reparative cellular states. During sustained elevation of cytosolic lactate, histone lactylation suppresses pro-inflammatory gene programs (including TNF-α and IL-6) and activates reparative gene expression — including VEGF and TGF-β — in macrophages and tubular epithelial cells [29, 34]. This represents a negative feedback mechanism through which cells experiencing metabolic stress signal a transition toward resolution. In the kidney, tubular cell lactylation under conditions of AKI-associated hyperlactatemia may modulate the expression of metabolic and inflammatory genes, potentially influencing the trajectory of renal recovery versus progression to fibrosis.

The clinical implication is significant: sustained hyperlactatemia in septic AKI is not merely an epiphenomenon of clearance failure, but an active modifier of gene expression programs in injured cells. The duration and magnitude of hyperlactatemia — not only its peak level — may influence renal repair trajectories through this mechanism. Further studies are needed to characterize the enzymatic mediators, target genes, and functional consequences of lactylation in human septic AKI.

Clinical interpretation and implications

The integration of renal metabolism into lactate physiology has important clinical implications. Elevated lactate concentration should be interpreted as a composite signal reflecting both production and clearance — not a specific marker of global tissue hypoxia. During the hyperacute phase of septic shock, tissue hypoxia is likely dominant and must be addressed promptly. However, persistent hyperlactatemia after hemodynamic optimization may predominantly reflect ongoing stress glycolysis, mitochondrial impairment, and reduced hepatic or renal lactate utilization — mechanisms unresponsive to further volume loading or vasopressor escalation.

Importantly, continued resuscitation aimed solely at normalizing lactate beyond established hemodynamic endpoints may be associated with harm. Emerging evidence suggests that aggressive lactate-normalization strategies in stabilized patients may contribute to fluid overload and organ dysfunction rather than benefit [32, 35]. This reinforces the importance of contextual interpretation: lactate levels should be integrated with clinical, hemodynamic, and renal functional data rather than treated as an independent resuscitation target.

Renal replacement therapy (RRT) can remove lactate by diffusion and convection; however, extracorporeal lactate clearance typically contributes only modestly to systemic lactate removal compared with endogenous metabolic disposal [36]. RRT may indirectly influence lactate kinetics by correcting acid-base disturbances and supporting homeostasis, but should not be viewed as a primary therapy for hyperlactatemia.

Urinary lactate as a potential marker of renal metabolic dysfunction (Fig. 2)

Urinary lactate has emerged as a potential marker of renal metabolic dysfunction in AKI, particularly where proximal tubular metabolism is impaired. In experimental models of ischemic and septic AKI, increased urinary lactate excretion has been associated with tubular injury and altered metabolic pathways [37]. Clinical studies in cardiac surgery have suggested that elevated urinary lactate early after cardiopulmonary bypass may predict AKI, potentially reflecting impaired proximal tubular lactate handling [16, 37].

A critical interpretive challenge must be acknowledged: because lactate is freely filtered at the glomerulus, systemic hyperlactatemia can overwhelm the proximal tubule’s reabsorption capacity, producing a ‘spillover’ effect in which elevated urinary lactate reflects increased filtered load rather than intrinsic tubular reabsorption failure or metabolic dysfunction. Current clinical evidence is insufficient to reliably distinguish spillover from genuine tubular reabsorption or metabolic defect in the septic patient, as the two mechanisms may coexist and cannot be separated by urinary lactate measurements alone.

Urinary lactate concentration is additionally influenced by urine flow rate and dilution, and should be expressed as a lactate-to-creatinine ratio. Even so, the ratio may partly reflect systemic hyperlactatemia rather than tubular dysfunction. Urinary lactate should therefore be regarded as an investigational biomarker that may complement — but not replace — established markers of tubular injury and stress (NGAL, KIM-1, TIMP-2/IGFBP7) [29]. Studies specifically designed to separate spillover from tubular-intrinsic mechanisms — using paired plasma and urinary lactate measurements alongside tubular functional markers — are needed before urinary lactate can be incorporated into clinical decision-making.

Conclusions

Hyperlactatemia in sepsis and shock reflects a complex interplay between increased production, altered utilization, and impaired clearance. While tissue hypoxia remains a dominant mechanism during the hyperacute phase, the relative contribution of clearance-limited mechanisms increases as resuscitation proceeds. The kidneys play a pivotal role in lactate metabolism through proximal tubular oxidation and gluconeogenesis, and septic AKI may shift lactate balance toward a clearance-limited phenotype contributing to persistent hyperlactatemia despite resuscitation. The metabolic heterogeneity of septic AKI — spanning mitochondria-capable and mitochondrially-impaired phenotypes — determines the degree to which renal lactate clearance is preserved or lost. Emerging evidence for lactylation-mediated gene regulation adds a further dimension to lactate’s role as an active signaling molecule in the injured kidney. Viewing lactate through a renal metabolic framework may refine interpretation of lactate kinetics, inform resuscitation endpoints, and motivate future studies quantifying organ-specific lactate flux and renal metabolic phenotypes in septic shock.

Take home message: “Viewing lactate through a renal metabolic lens reveals hyperlactatemia as an integrated signal of stress metabolism and impaired clearance — rather than a surrogate of hypoxia alone — with important implications for the interpretation and management of septic acute kidney injury.”

Abbreviations

SGLT2

Sodium–glucose cotransporter type 2

MCTP1-2

Multiple C2 domains and transmembrane region protein (MCTP) family, which stands for SMCT1-2, sodium-coupled monocarboxylate transporters 1 and 2

TCA

Tricarboxylic acid cycle

Author contributions

DP choose the topic and wrote the manuscript, TR and HG managed the manuscript, improved the editing, and helped to draw the figures.

Funding

Not applicable.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consnt to participate

Not applicable.

Consent for publication

All authors agreed.

Competing interests

The authors declare no competing interests.