This editorial refers to “Acute kidney injury in the critically Ill traumatic brain injury patients: A single center retrospective cohort study” by Wankhade et al, 2025; https://doi.org/10.5492/wjccm.v14.i4.110079.
INTRODUCTION
The management of traumatic brain injury (TBI) has progressed significantly, guided by technological advancements and standardized protocols[1]. However, achieving the best outcomes in these patients requires more than just high-quality intensive care. While the initial focus rightly centers on reducing primary and secondary brain insults, a deeper understanding of both beneficial and detrimental systemic factors is crucial to promoting patient recovery. The central challenge is recognizing that TBI triggers a complex, body-wide cascade of events. Non-neurological complications are rampant and significantly impair recovery[2]. Major systemic issues, including acute respiratory dysfunction, cardiovascular instability, sepsis, and acute kidney injury (AKI), often determine the patient’s ultimate prognosis[2,3]. This realization underscores the need to move beyond the immediate “what kills first” approach. Systemic complications often represent silent threats that develop beneath the surface of the primary injury. Consequently, clinical efforts and research must be refocused to understand the pathophysiology better, identify risk factors and predictors in order to develop integrated therapeutic strategies that address both the neurological problem and the systemic sequelae to improve both survival and functional outcomes. By addressing these issues proactively, healthcare providers can improve patient outcomes and ensure more efficient resource utilization.
INCIDENCE
The relationship between the brain and kidney - the neuro-renal crosstalk - is intricate and bidirectional, which is gaining significant clinical attention due to its association with poorer outcomes[4]. The reported incidence of AKI in patients with moderate to severe TBI ranges from 8% to 23%, with rates escalating sharply among those requiring intensive care or mechanical ventilation[2,5]. Significant variations exist in the reported incidence of AKI following TBI, primarily due to the heterogeneity of the underlying studies regarding both the definitions used and the patient populations investigated. Reported incidence often ranges from 11.9% to 26.7% when utilizing the Kidney Disease: Improving Global Outcomes (KDIGO) criteria based solely on serum creatinine changes. And an average of 17.7% when incorporating both serum creatinine and urine output components of the KDIGO definition[6]. In a study conducted by Huang et al[6], significant differences in AKI diagnosis were observed depending on the criteria used. The highest incidence of AKI was detected using the KDIGO (17.7%), closely followed by the acute kidney injury network criteria (17.1%). Rates were lower when applying the older criteria: Risk, injury, failure, loss, and end-stage kidney disease (risk 12.7%) and the creatinine kinase criteria (11.5%)[7]. Studies with narrower observation windows tend to report lower figures. For instance, Goyal et al[2] observed a lower incidence of 3.5%, likely because their surveillance period was restricted only to the patient’s stay in the intensive care units, whereas many investigations tracked the risk of AKI throughout the entire hospital course. Age of the patient population can be a critical determinant, as observed by Wankhade et al[8] where the older cohort > 50 years had a higher incidence of AKI, reaching upto 28%. Mortality as high as 80% has been reported in TBI patients with AKI, with the highest risk in those with severe AKI[2,7-10].
PATHOPHYSIOLOGY
AKI in TBI isn’t just secondary to trauma/shock - it is an interplay of multiple factors that collectively amplify the functional disruption of both these organs. This disruption is collectively driven by a confluence of neurogenic, hemodynamic, inflammatory, and iatrogenic factors, compounded by existing patient co-morbidities. Figure 1 maps the complex interplay driving this organ dysfunction. While the underlying pathophysiology is becoming increasingly understood, current literature offers limited data on specific interventions proven to prevent AKI in TBI patients. This raises a fundamental clinical question: Does the mere identification of predictors and risk factors effectively translate into actionable strategies for AKI prevention in this cohort?
Figure 1
Demonstration of the neuro-renal cross-talk.
Effective management of AKI following TBI necessitates a precise, multi-pronged approach skillfully balancing two critical physiological priorities - the cerebral perfusion and the renal perfusion. While the foundational principles of AKI care - early diagnosis and hemodynamic optimization - are universal, their application in the TBI population must rigorously account for intracranial pressure dynamics. In their retrospective study of 331 patients, Wankhade et al[8] reported that the presence of shock, elevated ICP, high Charlson Comorbidity Index, and high APACHE II scores were the main predictors of AKI after TBI. Similarly, several studies have investigated the risk factors predicting the development of AKI following TBI, and the most frequently recognized contributors include Advanced age, hemodynamic instability, Rhabdomyolysis and red blood cell transfusions[4-7,10]. However, important determinants of AKI - such as the adequacy of early resuscitation, fluid balance, vasopressor exposure, and nephrotoxic medications - have not been comprehensively evaluated in many studies, including that of Wankhade et al[8]. Addressing these factors may provide important insights into preventive strategies and improved management of AKI in this high-risk population.
THE HEMODYNAMIC PARADOX
There is essentially a “tug-of-war” between cerebral perfusion pressure and renal venous congestion, leading to a hemodynamic paradox in TBI patients with AKI. Barea-Mendoza et al[4] demonstrated that increasing age combined with refractory shock creates an adverse combination, contributing to markedly poor patient outcomes. Major guidelines underscore the need for maintaining systolic blood pressure (SBP) at a minimum of 13.33 kPa, with a higher target of ≥ 14.66 kPa in the elderly population[10]. The role of shock (hypotension) as a primary risk factor for AKI in TBI is indisputable. However, current research often treats shock as a simple binary event. To move beyond merely reactive treatments and develop targeted interventions, future studies must focus on quantifying the patient’s precise hemodynamic exposure to inadequate perfusion.
This requires shifting research focus to more specific details, such as cumulative duration of hypotension and the resuscitative strategies employed. It’s not just the occurrence of a single hypotensive episode, but the total time spent below critical SBP or mean arterial pressure thresholds that likely determines renal damage. An in-depth look is required to quantify the cumulative burden of hypotension across the first 24 hours to 48 hours post-injury. This precision would better link the dose of the hemodynamic insult to the risk of AKI development.
Additionally, the management of shock itself needs detailed scrutiny. Research should analyze the specific interventions used to restore perfusion, viewing them as both treatments and potential risk factors. A high vasopressor requirement is a marker of refractory shock, but the agents themselves can induce renal vasoconstriction, acting as a direct nephrotoxic insult[11]. Though the choice of vasopressor use is similar to that of other critically ill patients, the fluid resuscitation strategy needs to be more cautious as both hypervolemia and hypovolemia are known to compromise cerebral perfusion pressure and renal perfusion, in addition to other complications[6]. Thus, the role of advanced hemodynamic monitoring must be explored, especially from this point of view, and integrated into current protocols for preventing and treating AKI following TBI, especially in the high-risk cohort. Conversely, managing hypertension requires equal caution, employing a targeted, stepwise approach to prevent both potential neurological dysfunction and AKI stemming from a sudden, significant reduction in SBP[5].
THE CHOICE OF FLUID DILEMMA
The optimal choice of fluid for resuscitation in TBI to prevent renal dysfunction remains a dilemma. Crystalloids have generally been shown to be superior to colloids. While balanced crystalloids have demonstrated efficacy in preventing AKI in other critically and non-critically ill populations, their use in TBI is complicated by the risk of their relative hypotonicity potentially worsening intracranial pressure[12]. Conversely, administering large volumes of normal saline can lead to hyperchloremic metabolic acidosis. High chloride load, in turn, has been linked to renal vasoconstriction and subsequent reduction in renal perfusion[13]. Since no single crystalloid has been definitively established as beneficial, further research should investigate whether a tailored combination of fluids - optimized for both cerebroprotection and renoprotection - offers an effective solution for this unique population.
RHABDOMYOLYSIS - AN OPPORTUNITY TO TARGET
Rhabdomyolysis has been reported to be a critical contributor to AKI following TBI, with a reported incidence ranging between 17% and 45%[14,15] and elevating the risks of organ dysfunction and mortality[16]. It frequently results from muscle compression due to blunt trauma, and although it is less common in cases of isolated head injury, it can be considerably worsened by factors such as dehydration, hyperosmolality, and prolonged immobilization secondary to coma. Diagnosis is based on elevated creatine phosphokinase (CPK) levels and the presence of myoglobinuria[15-17]. CPK serves as a sensitive indicator, often continuing to rise for several days after injury, whereas myoglobin has a short plasma half-life of only 1-3 hours and is typically eliminated from circulation within 6 hours[13].
Timely detection and management of rhabdomyolysis are essential to prevent AKI. Some studies advocate for forced alkaline diuresis using mannitol and sodium bicarbonate after initial volume resuscitation[15-17]; however, this approach must be carefully balanced to avoid volume overload, which could exacerbate intracranial pressure. In severe cases, hemodialysis has been shown to be of benefit[15,18]. Furthermore, the safety and efficacy of such interventions in TBI patients remain unproven. Therefore, the routine use of CPK and myoglobin screening, along with immediate, targeted treatment of rhabdomyolysis, warrants further clinical study - particularly regarding its potential for AKI prevention in this population.
TRANSFUSIONS - CAUSE OR EFFECT?
Transfusions of packed red blood cells have been identified across multiple trials as a predictor of AKI in TBI patients. However, the role of transfusions in AKI development must be interpreted with nuance since transfusions are primarily a response to severe trauma and massive hemorrhage. Consequently, their association with AKI is largely considered a reflection of the profound shock state and hypoperfusion endured by the kidneys. This distinction underscores that management should be dictated by the patient’s clinical and physiological status, moving beyond a simple debate of restrictive vs liberal fluid strategies based on transfusion volume alone. Another critical, often interrelated, factor is trauma-associated coagulopathy. Coagulopathy following TBI has been shown to be an independent prognostic factor[19,20]. Gao et al[21] have demonstrated that this is also strongly associated with AKI[21]. Interestingly, some studies have shown that early transfusion of fresh frozen plasma may offer a protective effect against AKI development[4]. This benefit is believed to occur through improved hemodynamics and limited progression of intracranial injuries. This finding highlights a potential opportunity: The role of early viscoelastic testing and subsequent appropriate coagulation factor correction, which needs further dedicated studies, specially concerning its impact on AKI prevention and survival benefit[22,23].
THE RENAL REPLACEMENT STRATEGY
The use of renal replacement therapy (RRT) for AKI in patients with TBI remains infrequent[24,25]. Although the indications for starting RRT are consistent with those for any critically ill patient with AKI - such as refractory hyperkalemia, severe acidosis, or volume overload - ongoing concerns exist regarding the optimal timing and safety profile of the different modalities available. Nonetheless, these risks should not prevent the initiation of RRT when it is clinically warranted. Intermittent hemodialysis may induce rapid osmotic changes that can result in cardiovascular and intracranial instability. In contrast, continuous RRT is generally preferred because it provides greater hemodynamic stability and more gradual solute clearance. To further reduce risks, clinicians can utilize lower blood flow rates and effluent doses along with regional citrate anticoagulation to limit acute osmotic shifts and reduce systemic bleeding risk, respectively[6]. While definitive evidence for a mortality benefit between early and late continuous RRT initiation is lacking, the decision to commence RRT should be individualized. The treating team should base this decision on each patient’s clinical course rather than adhering to a predetermined timeframe[26].
THE FUTURE
The search for reliable predictive biomarkers remains a highly promising and potentially transformative area of research in TBI management. While these markers have traditionally been used to assess injury severity, recent research now explores their capacity to predict overall patient outcomes and systemic complications. Biomarkers such as S100B, glial fibrillary acidic protein, neurofilament light chain, and tau proteins are currently under investigation for both diagnostic applications and neurological prognostication[27,28].
S100B, in particular, stands out due to its predictive value beyond the central nervous system. Released from damaged astroglial cells, S100B has also been shown to help identify non-neurological complications[29]. Elevated peripheral levels of S100B may thus serve as a practical indicator of the systemic inflammatory response, potentially linking brain injury to remote organ dysfunction[30]. Integrating these biomarkers into clinical practice could be transformative, offering substantial benefits for early intervention and improved patient outcomes. Although many prognostic models exist to enhance functional outcomes in moderate to severe TBI, few have demonstrated sufficient robustness across multiple external validation cohorts[31]. The development of artificial intelligence-based prediction models, especially when combined with biomarker data, is a promising and necessary next step toward improving outcomes for patients with TBI.
CONCLUSION
While the standardization of TBI protocols represents a triumph of neurocritical care, the battle for patient survival is increasingly fought on a systemic front. Neurological recovery is inextricably bound to systemic stability, where complications like AKI do not merely accompany TBI - they dictate mortality, emphasizing the need for interdisciplinary collaboration. We must transcend our traditional focus on immediate life threats. The next revolution in TBI care demands a paradigm shift: Moving from reactive management to proactive prediction and prevention, and future research must prioritize this. Only by targeting the full spectrum of pathophysiology can we bridge the gap between simply surviving the injury and meaningful holistic recovery.
Peer review: Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Critical care medicine
Country of origin: India
Peer-review report’s classification
Scientific quality: Grade A
Novelty: Grade A
Creativity or innovation: Grade B
Scientific significance: Grade B
P-Reviewer: Álvarez-Maldonado P, MD, Academic Fellow, Professor, Research Dean, Mexico S-Editor: Bai SR L-Editor: Filipodia P-Editor: Lei YY
